Molecular and clinical aspects of histone-related disorders

Abstract

Epigenetics is the coordination of gene expression without alterations in the DNA sequence. Epigenetic gene expression is regulated by an intricate system that revolves around the interaction of histone proteins and DNA within the chromatin structure. Histones remain at the core of the epigenetic gene transcription regulation where histone proteins, along with the histone modification enzymes, and the subunits of chromatin remodelers and epigenetic readers play essential roles in regulating gene expression. Histone-related disorders encompass the syndromes induced by pathogenic variants in genes encoding histones, genes encoding histone modification enzymes, and genes encoding subunits of chromatin remodeler and epigenetic reader complexes. Defects in genes encoding histones lead to the expression of abnormal histone proteins. Abnormalities in genes encoding histone modification enzymes result in aberrant histone modifications. Defects in genes encoding subunits of the chromatin remodeler complexes result in defective chromatin remodeling. Defects in genes that code for the epigenetic readers (bromodomain proteins) will hinder their ability to regulate gene transcription. These disorders typically present manifestations that impact the nervous system which is particularly sensitive due to its need for specific patterns of gene expression for neural cell function and differentiation. To date, 72 histone-related disorders have been described including 7 syndromes due to defects in histone genes, 35 syndromes due to histone modifications defects, 26 syndromes due to defects in chromatin remodeling, and 4 due to defects in epigenetic readers. In this review article, the molecular basis of histone structure and function is first explained, followed by a summary of the histone-related syndromes.

Introduction

Alterations in gene expression are the reason behind a cell’s ability to differentiate into several cell types and have distinctive functions, despite having the same DNA sequence. Epigenetics describes the study of modifying gene expression without changing the DNA sequence itself. Epigenetic modifications are reversible, unlike permanent genetic variants in the DNA sequence. Epigenetic gene expression regulation is controlled by an intricate system that revolves around the interaction between DNA and histone proteins within the chromatin structure [1].

Epigenetic gene expression regulation involves changes in patterns of DNA methylation, histone modification, and chromatin remodeling. DNA methylation often corresponds to the repression of transcription while transcriptionally active DNA often remains unmethylated [2]. Chemical modifications of histone proteins, mediated by a battery of specialized enzymes, change the accessibility of DNA segments which also regulates the transcription process [3]. Chromatin remodeling is the process of changing the structure of the chromatin, mediated by remodeler complexes, to regulate DNA accessibility and gene expression (4).

Histones remain in the center of the epigenetic gene transcription regulation. For proper gene expression, it is mandatory to have structurally normal histones with the enzyme battery functioning on histone modification and the chromatin remodeler complexes mediating the dynamic interaction between histones and DNA in the chromatin structure. Histone-related disorders encompass the syndromes due to pathogenic variants in genes encoding histones, genes encoding histone modification enzymes, and genes encoding subunits of chromatin remodeler and epigenetic reader complexes. Defects in genes encoding histones lead to the expression of abnormal histone proteins. Abnormalities in genes encoding histone modification enzymes result in aberrant histone modifications. Defects in genes coding for the subunits of the chromatin remodeler complexes result in defective interaction between histones and DNA within the chromatin structure. Defects in genes that code for the epigenetic readers (bromodomain proteins) will hinder their ability to regulate gene transcription [5,6,7,8,9].

Defects in histone genes, histone modifications, chromatin remodeling, and epigenetic readers can cause disruptions in normal gene expression regulation. The regulation process plays a key role in activating or silencing genes needed for normal development. An essential part of organ formation is driven by coordinated changes in gene expression through regulated epigenetic modifications. Therefore, defects in histone genes, histone modifications, chromatin remodeling, and epigenetic readers can lead to the improper expression of genes and disrupt the normal process of development. This can trigger multiorgan manifestations with a significant impact on the nervous system which is especially susceptible due to the need for specific patterns of gene expression for neural cell function and differentiation [6].

To date, 72 histone-related disorders have been described including 7 syndromes due to defects in histone genes, 35 syndromes due to histone modifications defects, 26 syndromes due to defects in chromatin remodeling, and 4 due to defects in epigenetic readers. In this review article, the molecular basis of histone structure and function is first explained, followed by a summary of the histone-related syndromes. Finally, as these disorders share a broad common etiology which is an aberrant gene expression regulation, we compared these syndromes to highlight the overlapping features among them.

Molecular basis

Nucleosomes are made up of 146 base pairs of DNA surrounding an octamer of eight core histone proteins (two copies each of H2A, H2B, H3, and H4) with around 50 base pairs of DNA separating each pair of nucleosomes. Additionally, the H1 histone proteins, called linker histones, adhere to the DNA entry/exit points on the surface of the nucleosomal core particle and complete the nucleosome structure. H1 histones influence the nucleosomal repeat length (distance between the neighboring nucleosomes) and support the stabilization of higher-order chromatin structures as nucleosomes compact into a chromatin fiber, eventually forming a chromosome. Each histone protein has a flexible tail that protrudes from the nucleosome. The flexible tails of the histone proteins serve an essential function in the regulation of chromatin structure and function. These tails are subject to different post-translational modifications, such as acetylation and methylation. The interaction between positively charged amino acids in the tails (lysine, arginine, and histidine) attracts the negative charges on the DNA phosphates, keeping the DNA bound to histones [10,11,12,13].

Histone genes

Histones, which constitute about half of the mass of eukaryotic chromosomes, are a family of basic proteins that are highly abundant and among the most evolutionarily conserved in eukaryotic cells. In eukaryotic cells, multiple gene copies code for most histones and are categorized into clusters across various chromosomes. Among the five major families of histones, H2A, H2B, H3, and H4 are categorized as core histones, while H1 is known as linker histones [14, 15]. All core histones exist as dimers, in which they all contain a histone fold domain made up of three alpha helices connected by two loops. This helical structure enables the interaction between distinct dimers, specifically in a head–tail arrangement (also called the handshake motif) [16]. DNA wraps around the core histones, forming the nucleosome, while linker histones bind to the inter-nucleosomal DNA space [12].

Histones are encoded by several genes, and they can be classed into replication-dependent and replication-independent categories. As the cell enters the S-phase, replication-dependent histone genes are expressed to supply the histones necessary to support DNA replication. In contrast, replication-independent histone genes are typically expressed during the entirety of the cell cycle [12].

Replication-dependent histone genes are organized into four distinct genomic loci. The largest cluster, Cluster 1, is located on chromosome 6p22.1 and 6p22.2 (HIST1 locus), containing about 80% of the total histone genes. Cluster 2 is located on chromosome 1q21.2 (HIST2 locus), and Cluster 3 is located on chromosome 1q42.13 (HIST3 locus). Cluster 4 is found on chromosome 12p12.3 (HIST4 locus) and includes only one gene encoding the H4 core histone [17]. These replication-dependent genes are localized within a nuclear structure called the histone locus body (HLB), where histone mRNA transcription and processing occur. The protein NPAT (nuclear protein, coactivator of histone transcription) is essential for HLB formation and histone gene activation. As cells approach the S-phase, NPAT binds exclusively to these genes and activates their expression. Replication-dependent histone genes typically encode non-polyadenylated mRNA that ends in a stem-loop structure instead of a poly(A) tail [18, 19].

In contrast, replication-independent histone genes, which are typically expressed during the entirety of the cell cycle and transcribed into polyadenylated mRNAs, are scattered across the genome, usually as single copies, and are not associated with NPAT. An exception is the H2AX gene, which produces both a polyadenylated mRNA and a stem-loop mRNA during S-phase, although it is not considered replication-dependent due to its lack of NPAT binding [20,21,22] (Table 1).

Table 1 Histone genes and associated syndromes

The term "clustered" also refers to replication-dependent histones, which are organized into specific gene clusters and are integrated into the chromatin during DNA replication. These histones were previously referred to as "canonical" histones, but this term has been phased out to avoid confusion, as it may have different interpretations among researchers. On the other hand, replication-independent histones are not clustered, are scattered across the genome, and can be incorporated into chromatin independently of DNA replication, providing additional layers of chromatin regulation and functional diversity. This distinction between clustered replication-dependent histones and dispersed replication-independent histones highlights the complexity and specialization within the histone family, reflecting their unique roles in chromatin structure and function [19].

Previously, the replication-dependent histone genes nomenclature was determined by the genomic cluster in which the genes were found. For example, genes in the largest cluster were labeled as HIST1, such as HIST1H2AA, representing the first H2A gene in this cluster. Smaller clusters were labeled as HIST2, HIST3, and HIST4, with corresponding examples like HIST2H2BB for a gene in cluster 2. This cluster-based naming system provided consistent symbols for human and mouse orthologs but could be confusing for those unfamiliar with histone genes. The gene symbols, which were often long (e.g., HIST1H2AA), could be mistaken for representing histone types rather than their cluster, and the length of the symbols was seen as cumbersome, especially in clinical settings. Additionally, the cluster-based names did not apply to non-mammalian vertebrates. As seen in species like chickens, they exhibit a large, singular replication-dependent histone cluster [23, 24]. In contrast, replication-independent histone genes adopted a different nomenclature that began with the histone type, followed by ‘F’ for family, and an identifying letter. For instance, H2AFZ was used for the first human gene coding for the H2A.Z variant, and H2AFY for the gene encoding the macroH2A subtype. While this system was more straightforward in indicating histone types, it was separate from the replication-dependent gene nomenclature, leading to inconsistency across the histone gene family. The new naming system aims to address these issues by unifying the gene family under a common root symbol, simplifying the naming process, and making it more universally applicable across species [19, 25, 26] (Table 1).

Linker H1 histone

H1 histone genes begin with the root "H1″, and this nomenclature aligns with the protein nomenclature. Each H1 variant is identified by a distinct number, reflecting that every H1 gene codes for a unique histone protein. Consequently, the approved gene symbols correspond directly with the H1 protein symbols, for example, the H1-1 gene encodes the H1.1 protein [27]. In human gene symbols, hyphens are used in place of periods to separate numbers when necessary. All replication-dependent H1 genes are located in Cluster 1 [19] (Table 1).

Core histone H2A

The two primary classes of H2A proteins, H2A.1 and H2A.2, were initially distinguished by the variation of the 51st position of the protein sequence. These are encoded by several replication-dependent H2A histone genes. Most genes in the largest replication-dependent cluster, HIST1, encode H2A.1 proteins, whereas the HIST2 cluster encodes H2A.2 proteins. The smaller HIST3 cluster encodes an H2A.1 protein with additional amino acid changes [28]. The modified nomenclature does not differentiate between H2A.1 and H2A.2, creating a standardized ortholog nomenclature across vertebrate species. The replication-dependent H2A genes have been named with the root symbol "H2AC#" for "H2A clustered histone", for example, H2AC1 [19].

The protein nomenclature has been precisely followed for replication-independent H2A histones [29]. The human genes coding for the H2A.Z variant, observed in all eukaryotes, are named H2AZ1 and H2AZ2. The macroH2A variant, named so for being significantly larger than replication-dependent H2A histones, has subsequent gene symbols MACROH2A1 and MACROH2A2. Despite the "H2A" root symbol, these names are accepted by the histone community [30]. The H2AX gene is located outside replication-dependent clusters and codes for two unique mRNAs: one ending in a stem-loop and the other polyadenylated. The H2AX gene is not bound by NPAT, differentiating it from clustered genes. The H2AJ gene is not classified within an independent clade and encodes the H2A.J histone which is replication-independent. This gene exclusively produces polyadenylated mRNA and is positioned next to the H4C16 gene in Cluster 4 [31].

Short H2A histones are missing the C-terminal region in comparison to replication-dependent histones and are mainly expressed in the testis, with H2A.B also expressed in the brain [32]. Four genes encode short H2A histones. The H2AP gene encodes the H2A.P histone; and three paralogs H2AB1, H2AB2, and H2AB3 encode H2A.B histones. H2AB2 and H2AB3 encode identical proteins, while H2AB1 encodes a protein with one amino acid difference. These histones are sometimes known as H2A.B.1 and H2A.B.2 [33] (Table 1).

Core histone H2B

In line with the naming conventions for replication-dependent H2A genes, H2B genes on replication-dependent clusters are designated with the root symbol H2BC# for ‘H2B clustered histone’ [27]. Regarding H2B replication-independent histones, the H2B.W histone is represented by two paralogs, H2BW1 and H2BW2, found on the X chromosome. The H2BK1 gene encodes the H2B.K histone and the H2BN1 gene codes for the H2B.N histone. Additionally, a duplication of the H2BC12 gene is present on chromosome 21, named H2BC12L for "H2B clustered histone 12 like," as the encoded protein closely resembles the clustered histone, although explicit evidence of protein production is not available [34,35,36,37,38] (Table 1).

Core histone H3

Histone H3 genes on major replication-dependent clusters are designated with the root symbol ‘H3C#’ for “H3 clustered histone” [27]. The revised nomenclature uses H3.1 and H3.2 for histone proteins encoded on larger replication-coupled clusters. Nevertheless, this difference is not represented in the gene nomenclature to ensure consistency across orthologs in species. For example, human H3C2 encodes H3.1 protein, while other human genes may encode an H3.2 protein. The proteins are identical except for a cysteine at position 96 in H3.1 and a serine in H3.2 [19]. Regarding replication-independent H3 genes, the H3.3 histone is encoded by two genes H3-3A and H3-3B [39].

H3-like centromeric histone, encoded by the CENPA gene, is located at the nucleosome core of centromeric chromatin [40]. This protein replaces histone H3 in the nucleosomes of active centromeres in all eukaryotes. They are found in centromeric nucleosomes and are needed for the formation of the kinetochore, a network of proteins that ensures the correct segregation of chromosomes during nuclear division [41] (Table 1).

Core histone H4

The genes coding for histone H4 proteins are primarily located within replication-dependent clusters and are designated with the root symbol H4C# for “H4 clustered histone”. All human H4 genes code for the same protein [22]. The H4C16 gene is the only gene that belongs out of the primary mammalian replication-dependent clusters and codes for the same protein as other H4C genes. The H4C16 and H2AJ genes are adjacent, being one exon, and encode an mRNA with a stem-loop and a protein like the other H4C genes. It is expressed at elevated levels in all examined cells, is cell-cycle regulated like replication-dependent genes in bigger clusters, and is linked by NPAT, a factor that exclusively attaches to the promoters of replication-dependent histone genes [18, 42] (Table 1).

Histone modifications

To precisely regulate gene expression, various modifying enzymes, occasionally operating successively or in unison, create cell-type-specific epigenomes. These epigenomes impact chromatin condensation and accessibility to nucleosome-free DNA segments, which, in turn, affect the transcription process. Two main groups of regulators maintain a delicate balance in this process. Permissive marks, such as DNA demethylation and the addition of acetyl groups to histone tails, promote active euchromatin, which is a loosely packed and transcriptionally active form of chromatin. On the other hand, repressive marks, including DNA methylation and histone deacetylation, favor inactive heterochromatin, which is compact and inaccessible to transcription factors. Additionally, histone methylation can lead to either transcriptional activation or repression [3].

Histone modification involves modifications to the tails of histone proteins through the incorporation or removal of methyl or acetyl groups. These modifications can influence chromatin dynamics by altering the interaction between histones and DNA, as well as by recruiting other proteins that are engaged in the remodeling of the chromatin and gene expression, like transcription factors [10,11,12,13].

Histone methylation and demethylation

Methylation of histones mainly takes place on lysine (K) residues in histones H3 and H4, specifically on the nitrogen atoms of their side chains. The addition or removal of methyl groups is both reversible and highly dynamic. It is regulated by two key enzyme groups: histone lysine methyltransferases (KMTs), responsible for adding methyl groups, and histone lysine demethylases (KDMs), which remove them [3].

The consequence of histone lysine methylation on gene expression is contingent on the exact lysine residue being modified. Typically, the methylation of histone H3 at lysine 4 (H3K4), H3K36, and H3K79 is affiliated with active-euchromatin, while methylation of H3K9, H3K27, and H4K20 is affiliated with inactive-heterochromatin [43, 44].

The KMT2 family, consisting of six members KMT2A (MLL1; mixed lineage leukemia 1), KMT2B (MLL2), KMT2C (MLL3), KMT2D (MLL4), KMT2F (SETD1A), KMT2G (SETD1B), is considered the primary H3K4 methyltransferases. These proteins possess enzymatic activity guided by the highly conserved SET (Su(var)3–9, Enhancer of zeste, and Trithorax) domain. The KMT2 proteins are organized into three pairs based on their methylation specificity and domain structure: KMT2A/B, KMT2C/D, and KMT2F/G. These proteins can mono-methylate H3K4 to form H3K4me1, di-methylate H3K4 to form H3K4me2, or tri-methylate H3K4 to form H3K4me3. KMT2A/B facilitates mono-methylation and di-methylation, KMT2C/D catalyzes mono-methylation, and KMT2F/G facilitates di-methylation and tri-methylation of H3K4. H3K4me1, H3K4me2, and H3K4me3 serve as distinguishing markers for genes being actively transcribed [45, 46].

Gene expression is also initiated by NSD enzymes and SETD2. The NSD (nuclear receptor-binding SET domain) family consisting of NSD1 (KMT3B), NSD2 (KMT3G), and NSD3 (KMT3F) along with SETD2 (KMT3A), are the major H3K36 methyltransferases. NSD enzymes are responsible for H3K36 mono-methylation and di-methylation while SETD2 can perform H3K36 trimethylation [3, 43].

The inhibition of transcription occurs from other histone lysine methyltransferases. They include KMT1D (EHMT1; euchromatic histone methyltransferase 1) which mono-methylates and di-methylates H3K9 and KMT6A (EZH2; enhancer of zeste homologue 2) which tri-methylates H3K27 [3, 43].

Each KMT2 protein forms a unique multi-subunit complex called the COMPASS (COMplex of Proteins Associated with Set 1) complex. All KMT2 COMPASS complexes share the WRAD (WDR5, RBBP5, ASH2L, and DPY30) complex, which interacts with the SET domain and significantly amplifies the catalytic activity of the methyltransferase by several 100-fold. The WRAD complex also contributes to the recruitment of these complexes to chromatin. Additionally, each complex contains specific non-WRAD subunits that influence their diverse biological activity and role. The KMT2 COMPASS complexes can be categorized into three subtypes: KMT2A/KMT2B (MLL1/MLL2), KMT2C/KMT2D (MLL3/MLL4), and KMT2F/KMT2G (SET1A/SET1B) complexes [47].

Recruitment of different COMPASS family members to chromatin occurs through various processes, including direct DNA binding, interaction with transcription factors, and interaction with histone modifiers. The direct interaction of KMT2 complexes with DNA impacts chromatin at promoters and/or enhancers. H3K4me2/me3 marks are predominantly found close to the promoters of transcriptionally active genes, while H3K4me1 is often localized to enhancer regions. These observations align with H3K4 methylation being linked to open or accessible chromatin, which facilitates the expression of genes. KMT2F/KMT2G complexes are primarily present at promoter sites, while KMT2C/KMT2D complexes are enriched in enhancer regions. KMT2A/KMT2B complexes are found at both promoters and enhancers [45, 47]. PROSER1 (proline and serine-rich protein) has been identified as a component of the KMT2C/KMT2D COMPASS complexes and has a key role in stabilizing these complexes [48].

TASP1 (threonine aspartase 1) greatly contributes to the activation of certain histone methyltransferases. TASP1 undergoes autocatalytic cleavage, resulting in the formation of two subunits: alpha and beta. These subunits combine to form the active heterodimeric endopeptidase enzyme. The active enzyme utilizes the N-terminal threonine at amino acid position 234 (p.Thr234) of the mature beta subunit as the active-site nucleophile for proteolyzing polypeptide substrates. Given its ability to cleave nuclear factors after an aspartate residue, it is referred to as threonine aspartase (taspase). Active TASP1 cleaves and activates histone methyltransferases belonging to the KMT2 protein family, such as KMT2A and KMT2B [49]. Thus, TASP1 serves as a key regulator of histone methylation [50].

Conversely, histone lysine demethylases (KDMs) carry out a contrary function of KMTs by removing methyl groups from histone lysine residues. For example, KDM1A (LSD1; lysine-specific demethylase 1) demethylates H3K4me1/me2. KDM5A, KDM5B, and KDM5C (JARID1C; Jumonji, AT rich interactive domain 1C) demethylates H3K4me2/me3, KDM6A (UTX; ubiquitously transcribed tetratricopeptide repeat, X chromosome) and KDM6B demethylates H3K27me2/me3, and KDM3B demethylates H3K9me1/me2. Additionally, KDM7B (PHF8; PHD finger protein 8) demethylates H3K9me1/me2 and H4K20me1 [3, 43].

Histone acetylation and deacetylation

Histone acetylation is mediated by histone acetyltransferases (HATs); these modifications are eliminated by histone deacetylases (HDACs). Alternative nomenclature for these enzymes can include lysine acetyltransferases (KAT) and lysine deacetylases (KDAC) because their enzymatic activities are not restricted to histone proteins [51, 52]. At this time, these acetyltransferases are grouped into three major families based on sequence conservation of the KAT domain and biological functions. The first group is the MYST family, which is an acronym of its founding members MOZ, Ybf2/Sas3, Sas2, and Tip60 enzymes and it includes five members: KAT5, KAT6A (formerly known as MOZ and MYST3), KAT6B (formerly known as MORF and MYST4), KAT7 and KAT8. The second group of HATs is referred to as CREBBP/EP300, and consists, as the name suggests, of the ubiquitously expressed CREB-binding protein (CREBBP; KAT3A) and its close relative EP300. The third group is the Gcn5-related acetyltransferase family (GCN5/PCAF, also known as KAT2A/KAT2B) [53, 54].

The reverse reaction of acetylation is facilitated by histone deacetylase (HDAC) [55]. HDAC enzymes are grouped into four classes. Class I HDACs comprise of HDACs 1–3, and 8, and their functions are limited solely to the nucleus. Class IIa HDACs (4, 5, 7, and 9) are transported between the nucleus and cytoplasm but possess no intrinsic deacetylase activity and are believed to serve as scaffolds for other co-repressor systems. Class IIb enzymes (6 and 10) primarily operate outside the nucleus, where they facilitate the deacetylation of cytosolic proteins. Class III HDACs consist of the sirtuin (SIRT) subfamily of enzymes that exist in the nucleus, cytosol, and mitochondria. Class IV HDACs currently consist of only the nuclear HDAC11. Deacetylation reactions are zinc-dependent for Class I, II, and IV enzymes, while Class III enzymes are dependent on NAD + as a cofactor [51].

Lysine acetylation destabilizes chromatin structure, causing it to assume a more open configuration (active-euchromatin). Whereas lysine deacetylation induces chromatin condensation and transcriptional repression. Under normal pH, histone lysine residues are positively charged which interact with the negatively charged DNA, establishing a strong bond between the DNA and the histone protein. This is further strengthened by histone deacetylation which reveals the positive charges, promoting stronger electrostatic interactions, and favors condensed-inactive-chromatin. Acetylation of lysine causes the depletion of its positive charge, thus, diminishing the interactions between histones and DNA, resulting in open-active-chromatin, promoting transcription factor recruitment and enhanced gene expression [56].

Chromatin remodeling

Chromatin, composed of DNA wrapped around histone proteins, can exist in a non-active tightly packed (heterochromatin) or active loosely packed (euchromatin) state. Chromatin remodeling is a dynamic process that modifies the configuration of chromatin to control DNA accessibility and gene expression. The main functions of chromatin remodeling are nucleosome assembly and organization, chromatin access, and nucleosome editing, which can either expose or obscure specific DNA regions from the cellular machinery responsible for transcription, replication, and repair. The importance of chromatin remodeling lies in its ability to regulate gene expression dynamically. It allows cells to respond to environmental signals, control developmental processes, and maintain cellular identity. Defects in chromatin remodeling have been correlated to numerous diseases, including neurological disorders, cancer, and developmental abnormalities, highlighting its crucial function in maintaining genomic integrity and proper cellular function [4].

Chromatin remodeling complexes (chromatin remodelers) are multi-subunit assemblies of proteins that regulate chromatin remodeling. Dynamic regulation of chromatin consists of four subfamilies of ATP-dependent chromatin remodeling complexes: imitation switch (ISWI), chromodomain helicase DNA-binding (CHD), switch/sucrose non-fermentable (SWI/SNF), and inositol requiring 80 (INO80) [4, 57]. Each chromatin remodeling complex has a particular interaction with transcription activators, repressors, and modified histones, which collectively establish targeting. The variation in chromatin remodeling complex function is based on the variability in the protein composition of remodelers. Each subfamily is dedicated to mainly achieving particular chromatin outcomes: nucleosome assembly and organization, chromatin access, and nucleosome editing [4, 57].

Although chromatin remodelers have diverse protein compositions and perform variable functions, all remodelers possess common characteristics. First, remodelers encompass a single catalytic subunit with an ATPase domain operating as a DNA translocase, disrupting histone-DNA links in nucleosomes. Second, they possess domains and/or subunits that regulate the ATPase domain and the translocation process, replacing DNA relative to the octamer, which means shifting the position of the DNA that is coiled around the histone core. Third, these remodelers present domains that bind histones and recognize particular histone modifications, leading to a higher affinity for the nucleosome compared to free DNA, thereby allowing potential regulation by these modifications. Fourth, remodelers include domains and/or subunits capable of binding free or extranucleosomal DNA, which provides additional information about the chromatin structure and guides the remodeling process. Lastly, these remodelers contain domains and/or subunits that interact with other chromatin factors, such as transcription factors or histone chaperones, contributing to targeting, which directs remodelers to specific chromatin sites where their activity is needed [58].

Nucleosome assembly and organization (ISWI and CHD subfamilies)

Following DNA replication, histone chaperones deliver histone complexes, specifically H3-H4 tetramers and H2A-H2B dimers, to the newly synthesized DNA behind the replication machinery. Here, assembly remodelers from the ISWI and CHD subfamilies play crucial roles in nucleosome formation. Firstly, these remodelers assist the preliminary histone-DNA complexes, known as pre-nucleosomes, to mature into fully formed octameric nucleosomes. Secondly, they organize these nucleosomes into arrays by keeping them spaced at relatively uniform distances apart. This facilitates the formation of tightly packed nucleosome arrays, thereby promoting gene silencing (transcription suppression) and maintaining chromatin structure. To achieve this, the motor subunits of the ISWI and CHD subfamilies possess a DNA-binding domain (DBD) or a HAND–SANT–SLIDE (HSS) domain, that plays a role in determining the spaces between nucleosomes. These subunits also interact with and are regulated by the tails of histone H4. The H4 tails are the flexible N-terminal ends of the H4 histone proteins that extend out of the nucleosome core and can endure various modifications. These modifications, such as acetylation and methylation, can influence nucleosome dynamics and remodeling activity. The members of the CHD subfamily CHD1, 2, 3, 4, 5, 7, and 8 have been linked to human diseases [57,58,59].

Chromatin access (SWI/SNF subfamily)

The SWI/SNF subfamily of chromatin remodelers primarily (but not solely) increases chromatin accessibility to proteins and RNA by carrying out multiple functions, therefore, they are access remodelers. These functions include sliding nucleosomes along the DNA, which involves repositioning the nucleosomes to expose different DNA regions; evicting nucleosome components, such as H2A-H2B dimers, which involves removing parts of the nucleosome structure; and ejecting full nucleosomes, which involves completely displacing nucleosomes from the DNA. By performing these functions, SWI/SNF remodelers can reveal binding sites for repressors or transcription activators at gene enhancers or promoters and enhance access to recombination factors and DNA repair [57].

On the other hand, assembly remodelers (ISWI and CHD subfamilies) which are explained before, facilitate gene silencing through the creation of tightly packed nucleosome arrays, thereby restricting access to the DNA and preventing transcription. Contrary to the ISWI and CHD subfamily remodelers, which are typically smaller complexes, the SWI/SNF subfamily remodelers are uniformly large multi-protein complexes. These complexes have a conserved modular subunit organization and nucleosome recognition mechanism across different complexes and organisms [4].

Catalytic subunits with an ATPase function (core motor subunits) of the SWI/SNF subfamily remodelers include SMARCA2 (SWI/SNF related BAF chromatin remodeling complex subunit ATPase 2) and SMARCA4 (SWI/SNF related BAF chromatin remodeling complex subunit ATPase 4). Other subunits stabilizing the complex and maintaining its integrity, regulating activity and mediating interactions with other proteins, and defining complex specificity include SMARCB1 (SWI/SNF related BAF chromatin remodeling complex subunit B1), SMARCC1 (SWI/SNF related BAF chromatin remodeling complex subunit C1), SMARCC2 (SWI/SNF related BAF chromatin remodeling complex subunit C2), SMARCD1 (SWI/SNF related BAF chromatin remodeling complex subunit D1), SMARCD2 (SWI/SNF related BAF chromatin remodeling complex subunit D2), SMARCD3 (SWI/SNF related BAF chromatin remodeling complex subunit D3) SMARCE1 (SWI/SNF related BAF chromatin remodeling complex subunit E1), ACTL6A (actin like 6A), ACTL6B (actin like 6B), DPF1 (double PHD fingers 1), DPF2 (double PHD fingers 2), DPF3 (double PHD fingers 3), PHF10 (PHD finger protein 10), ARID1A (AT-rich interaction domain 1A), ARID1B (AT-rich interaction domain 1B), ARID2 (AT-rich interaction domain 2), PBRM1 (polybromo 1), BRD7 (bromodomain containing 7), BRD9 (bromodomain containing 9), BICRA (BRD4 interacting chromatin remodeling complex associated protein), and BICRAL (BICRA like chromatin remodeling complex associated protein) [60]. ATRX (ATRX chromatin remodeler) is a related member that functions as the catalytic component of the chromatin remodeling complex ATRX: DAXX which has ATP-dependent DNA translocase activity and catalyzes the replication-independent deposition of histone H3.3 in pericentric DNA repeats outside S-phase and telomeres [61].

Nucleosome editing (INO80 subfamily)

The INO80 subfamily of chromatin remodelers is involved in a process known as nucleosome editing, which does not depend on DNA replication. This process involves removing a specific histone from a nucleosome and replacing it with either a clustered, replication-dependent histone or a non-clustered, replication-independent histone variant [4, 58]. An example of nucleosome editing is the replacement of clustered H2A-H2B dimers with H2A.Z1 non-clustered histone-containing H2A.Z1-H2B dimers. This replacement can occur at a single nucleosome or across multiple nucleosomes in a region of DNA. These changes can affect the recruitment, exclusion, and activity of various factors which can potentially alter the stability of the nucleosome and how it is recognized by other chromatin-associated proteins. Along with its function in histone replacement, the INO80 complex is also capable of repositioning nucleosomes along the DNA. This repositioning can influence gene expression and other DNA-related processes by making certain regions of the genome accessible to other regulatory proteins and transcription factors [4, 58].

INO80 is a catalytic ATPase subunit of the INO80 chromatin remodeling complex. RUVBL1 (RuvB like AAA ATPase 1) and RUVBL2 (RuvB like AAA ATPase 2) stabilize the complex. SRCAP (Snf2-related CREBBP activator protein) facilitates the replacement of H2A with H2A.Z in nucleosomes [62].

DNA repair

Along with gene expression regulation, chromatin remodeling complexes are vital for preserving genome integrity by altering chromatin structure to allow access to DNA damage sites. When DNA damage occurs, chromatin remodeling complexes such as SWI/SNF, INO80, and CHD are recruited to the damage sites. These complexes use ATP hydrolysis to reposition or evict nucleosomes, thereby exposing the DNA and facilitating the access of repair machinery. For instance, the INO80 complex participates in repairing double-strand breaks by homologous recombination, where it repositions nucleosomes to create an accessible chromatin environment for repair proteins to function efficiently. Similarly, the SWI/SNF complex is implicated in nucleotide excision repair, which helps remove bulky DNA lesions caused by UV light. Thus, chromatin remodeling is essential for effective DNA repair and upholding genomic stability [63, 64].

Epigenetic readers

Bromodomain proteins work as epigenetic readers as they recognize acetylated histone tails and facilitate the transcription of target genes. There are around 60 known human bromodomains that perform critical functions in chromatin remodeling and gene regulation by identifying and binding acetyllysine residues on histone tails projecting from the nucleosome [5].

Bromodomain-containing proteins influence chromatin dynamics through their many functional domains. They include BRPF (bromodomain and PHD finger-containing), BRD (bromodomain-containing), ATAD2 (ATPase family, AAA domain containing 2), and BRWD (bromodomain and WD repeat domain containing) proteins. Although they have diverse activities, these proteins' bromodomains have common structural characteristics that allow them to identify certain histone modifications, regulating gene expression and chromatin accessibility [5].

BRPF proteins

The BRPF (bromodomain and PHD finger-containing) proteins serve as scaffolds for histone acetyltransferase complexes. BRPF proteins are characterized by a bromodomain and a plant homeodomain (PHD), which facilitate chromatin interactions. BRPF1 plays a role in the KAT6A/KAT6B histone acetyltransferase complexes, responsible for acetylating histones H2A, H2B, H3, and H4. Meanwhile, BRPF2 and BRPF3 function as subunits of the KAT7 complex, which specifically acetylates histone H4 at lysine residues 5, 8, and 12 [5, 65,66,67].

Structurally, all BRPF proteins contain a specialized domain known as PZP, consisting of a double PHD domain separated by a zinc knuckle. While its physiological function remains unclear, it is known to preferentially bind to unmodified histone H3 and nucleosomal DNA [68,69,70]. BRPF proteins also contain a conserved C-terminal bromodomain, which shares significant sequence identity across the family. These proteins serve as scaffolding components within the KAT6A/KAT6B and KAT7 complexes, helping to recruit histone acetylation activity to chromatin. By integrating multiple epigenetic reader domains, they play a critical role in transcriptional regulation and epigenetic modifications [71].

BPTF (bromodomain PHD finger transcription factor) protein is a critical component of the nucleosome remodeling factor (NURF) complex. This protein is involved in a significant role in chromatin remodeling and epigenetic reading, as it contains both a bromodomain and a PHD finger, which facilitate interactions with acetylated histones and methylated DNA, facilitating the recruitment of other chromatin-modifying complexes. Through its role in the NURF complex, BPTF participates in the regulation of chromatin dynamics and gene expression at both the transcriptional and epigenetic levels [72, 73].

BRD proteins

The BRD (bromodomain-containing) proteins play a critical role in chromatin remodeling through their involvement in the SWI/SNF complex, which regulates gene expression. BRD7 is a subunit of the polybromo-associated BRG1-associated factor (PBAF) complex and interacts with BRCA1, influencing BRCA1-dependent transcription. Structurally, BRD7 is made of approximately 650 amino acids, with its bromodomain located near the N-terminus. Beyond its role in the SWI/SNF complex, BRD7 is also involved in regulating the p53 and PI3K pathways [5, 74,75,76,77,78,79]. BRD4 plays a key role in regulating gene expression by binding to acetylated histones through its bromodomains, which in turn affects chromatin structure and transcriptional activity. It is involved in several important biological processes, including transcription regulation, histone acetyltransferase activity, DNA repair, and cell cycle regulation. As a transcription regulator, BRD4 recruits transcription factors and RNA polymerase II to promoter regions, facilitating the elongation of both coding and enhancer RNAs. It possesses intrinsic histone acetyltransferase activity, which acetylates histones H3 and H4, leading to chromatin decompaction and transcriptional activation. Additionally, BRD4 is essential for the repair of DNA double-strand breaks by engaging the non-homologous end joining (NHEJ) pathway, ensuring genomic stability. Furthermore, it plays a role in cell cycle progression and mitotic bookmarking, ensuring the reactivation of transcription after mitosis [80,81,82,83].

ATAD2 proteins

The ATPase family, AAA domain-containing 2 protein (ATAD2) is involved in nucleosome remodeling and transcriptional control. It contains two conserved domains: an N-terminal AAA + ATPase domain and a C-terminal bromodomain. The AAA + (ATPase associated with diverse cellular activities) domain is composed of two alpha-helical subdomains responsible for ATP hydrolysis through nucleophilic attack on the gamma-phosphate. Proteins in the AAA + superfamily often assemble into hexameric ring complexes and participate in macromolecular remodeling. In ATAD2, this domain is essential for protein oligomerization and recognition of acetylated histones [84,85,86,87].

BRWD proteins

BRWD (bromodomain and WD repeat domain containing) proteins contain both bromodomain and WD repeats, and they play important roles in regulating histone modifications. One of its key functions for BRWD3 is promoting the degradation of histone demethylase KDM5 which helps to maintain the proper levels of H3K4 methylation. This regulation is essential for ensuring that gene expression remains balanced and appropriate. Additionally, BRWD3 negatively regulates the deposition of the histone variant H3.3 by the HIRA complex (a replication-independent histone chaperone), which is important for maintaining normal gene expression and preventing developmental defects [88,89,90].

Clinical syndromes

Histone proteins, along with the histone modification enzymes, and the chromatin remodeler complexes are essential for proper epigenetic gene expression regulation. Histone-related disorders encompass the syndromes caused by pathogenic variants in genes encoding histones, genes encoding histone modification enzymes, and genes encoding subunits of chromatin remodeler complexes. Defects in genes encoding histones lead to the expression of abnormal histone proteins. Abnormalities in genes encoding histone modification enzymes result in aberrant histone modifications. Defects in genes encoding subunits of the chromatin remodeler complexes result in defective interaction between histones and DNA within the chromatin structure. Defects in genes that code for the epigenetic readers will hinder their ability to regulate gene transcription [5].

Defects in histone genes, histone modifications, chromatin remodeling, and epigenetic readers will result in abnormal epigenetic gene expression regulation (defects in the activation and deactivation of gene expression). Organ development requires coordinated changes in gene expression, which is mainly facilitated by epigenetic modifications. Therefore, defects in histone genes, histone modifications, chromatin remodeling, and epigenetic readers can lead to the failure of specific gene expression disrupting proper developmental processes [51].

As defects in histone genes, histone modifications, chromatin remodeling, and epigenetic readers can result in the abnormal expression of a group of genes, histone-related disorders usually present with manifestations across multiple organs. The nervous system is exceptionally sensitive due to its need for dynamic patterns of gene expression that are required for neural cell function and differentiation [91]. Therefore, these aberrations have a profound influence on the nervous system, and neurodevelopmental impairments are features in most histone-related disorders [92].

To date, 72 histone-related disorders have been described including 7 syndromes due to defects in histone genes, 35 syndromes due to histone modifications defects, 26 syndromes due to defects in chromatin remodeling, and 4 due to defects in epigenetic readers (Table 2).

Table 2 Clinical manifestations of histone-related disorders

Histone gene defects

One syndrome has been associated with defects in one of the genes coding for the H1 linker histone and six syndromes were associated with defects in genes coding for core histones (Tables 1, 2).

Rahman syndrome (MIM#617637)

This syndrome is due to monoallelic pathogenic variants in the H1-4 gene (MIM*142220). It is an autosomal dominant disease; however, almost all the variants occurred de novo. It is associated with variable phenotypes.

Affected individuals have developmental delay, cognitive impairment, behavioral disturbances (attention deficit hyperactivity disorder, head banging, aggression, auditory hypersensitivity, anxiety, phobias, and obsessions), autistic features, overgrowth (at birth and postnatal), obesity, ocular anomalies (strabismus, astigmatism, amblyopia, and delayed visual maturation), hypotonia or hypertonia, macrocephaly, gastrointestinal anomalies (feeding difficulties in neonatal period and constipation), skeletal deformities (advanced bone age, decreased bone mineral density, camptodactyly, kyphoscoliosis, and talipes equinovarus), dry and flaky nails, dental abnormalities with crumbled teeth, dermatologic manifestations (redundant skin on the nevi and palms of the hands), facial dysmorphisms (telecanthus and full cheeks), and abnormal neuroimaging (slender corpus callosum and periventricular leukomalacia) [13, 93].

Bryant–Li–Bhoj neurodevelopmental syndrome

This neurodevelopmental syndrome is genetically heterogeneous and is associated with variable phenotypes. It occurs due to pathogenic variants in H3-3A causing Bryant–Li–Bhoj neurodevelopmental syndrome 1 or in H3-3B causing Bryant–Li–Bhoj neurodevelopmental syndrome 2.

Bryant–Li–Bhoj neurodevelopmental syndrome 1 (MIM#617920)

This syndrome is due to monoallelic pathogenic variants in the H3-3A gene (MIM*601128). It is an autosomal dominant disorder; however, all the variants occurred de novo [94].

Affected individuals have developmental delay, developmental regression, cognitive impairment, growth failure, hypotonia, hypertonia, seizures (febrile, generalized, tonic, clonic, complex partial, and focal; some are responsive and others refractory to therapy), movement abnormalities (ataxia and wide based gait), hearing impairment, ocular anomalies (esotropia, exotropia, oculomotor abnormalities, nystagmus, tracking problems, and strabismus), microcephaly or macrocephaly, cardiovascular malformations (atrial septal defect; ASD), skeletal deformities (scoliosis, craniosynostosis, bell shaped thorax, kyphosis, lordosis, contractures or joint hypermobility, small hands, camptodactyly, pes planus, and small feet), respiratory anomalies (laryngomalacia), genitourinary anomalies (cryptorchidism), gastrointestinal anomalies (feeding problems, gastroesophageal reflux, and chronic constipation), facial dysmorphisms (plagiocephaly, dolichocephaly, prominent or sloped forehead, bitemporal narrowing, flat midface, low-set and posteriorly rotated ears, arched eyebrows, synophrys, deep-set eyes, hypo or hypertelorism, epicanthal folds, short palpebral fissures, flat and depressed nasal bridge, small or large nose, microretrognathia, prognathism, open mouth, and tented upper lip), and abnormal neuroimaging (enlarged ventricles, hypomyelination, and hypoplastic corpus callosum) [94, 95].

Bryant–Li–Bhoj neurodevelopmental syndrome 2 (MIM#619721)

This syndrome is due to monoallelic pathogenic variants in the H3-3B gene (MIM*601058). It is an autosomal dominant disorder; however, all the variants occurred de novo [94].

Affected people exhibit developmental delay, cognitive impairment, growth failure or macrosomia, hypotonia, hypertonia, seizures, hearing impairment, ocular anomalies (strabismus, nystagmus, esotropia, and myopia), microcephaly or macrocephaly, skeletal deformities (abnormal skull shape, scoliosis, hemivertebrae, flat feet, and joint hypermobility or contractures), dental anomalies, genitourinary anomalies (cryptorchidism), endocrine anomalies (hypothyroidism, diabetes mellitus type 1, advanced bone age, and precocious puberty), facial dysmorphisms (brachycephaly, plagiocephaly, dolichocephaly, midface hypoplasia, prominent forehead, flat facial profile, large, posteriorly rotated and low-set ears, bushy eyebrows, deep-set eyes, long eyelashes, down-slanted palpebral fissures, smooth philtrum, protruding chin, micrognathia, high arched palate, open mouth, and thin upper lip), and abnormal neuroimaging (cortical atrophy or dysplasia, hypomyelination, leukoencephalopathy, and thin corpus callosum) [94, 95].

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome

This neurodevelopmental syndrome is genetically heterogeneous and is associated with variable phenotypes. It occurs due to pathogenic variants in H4C3 causing Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 1, in H4C11 causing Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 2, in H4C5 causing Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 3, or in H4C9 causing Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 4 [96].

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 1 (MIM#619758)

This syndrome is due to monoallelic pathogenic variants in the H4C3 gene (MIM*602827). It is inherited in an autosomal dominant pattern and most variants occur de novo [96].

Affected individuals have developmental delay, cognitive impairment (mild to severe), growth failure, autistic features, behavioral disturbances, psychiatric manifestations (psychosis and auditory hallucinations), movement abnormalities (ataxia), seizures, hypotonia, hearing impairment, ocular anomalies (myopia, strabismus, and hypermetropia), microcephaly, skeletal deformities (lordosis, brachycephaly, and dolichocephaly), dental crowding and widely spaced teeth, umbilical hernia, genitourinary anomalies (small kidneys, small renal cysts, and lack of corticomedullary junction), cardiovascular malformations (ASD, hypertension, thrombosis, and heart failure), facial dysmorphisms (broad nasal tip, smooth and wide philtrum, low-set ears, hypertelorism, up-slanted palpebral fissures, large mouth, and thin upper lip), cutis marmorata, and abnormal neuroimaging (decreased white matter) [96].

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 2 (MIM#619759)

This syndrome is due to monoallelic pathogenic variants in H4C11 (MIM*602826). It is an autosomal dominant disorder; however, all variants occurred de novo. Affected individuals exhibit developmental delay, cognitive impairment (profound), growth failure (short stature), hypotonia, ocular anomalies (oculomotor apraxia and esotropia), microcephaly, skeletal deformities (slender hands and flat feet), muscular anomalies (atrophy of limb muscles), facial dysmorphisms (arched eyebrows, periorbital fullness, hypertelorism, up-slanted palpebral fissures, short philtrum, flat nasal bridge, wide mouth, and downturned corners), and abnormal neuroimaging (prominence of cisterns and supratentorial sulci) [97].

Tessadori-Bicknell-van Haafterb neurodevelopmental syndrome 3 (MIM#619950)

This syndrome is due to monoallelic pathogenic variants in the H4C5 gene (MIM*602830). It is an autosomal dominant disorder; however, all variants occurred de novo [98]. All affected people exhibited developmental delay and intellectual disability. Other reported findings included behavioral disturbances, autistic features, growth failure, hypertonia or hypotonia, seizures, movement abnormalities (ataxia), hearing impairment, ocular anomalies (strabismus, astigmatism, and myopia), microcephaly, skeletal deformities (craniosynostosis, vertebral abnormalities, short toes, and toe syndactyly), abnormal teeth position with a gap between the central upper incisors, hematological anomalies (leukemia in 1 person), facial dysmorphisms (broad nasal tip, hypertelorism, up-slanted palpebral fissures, thin upper lip, and pointy chin), and premature aging [98].

Tessadori-Bicknell-van Haafterb neurodevelopmental syndrome 4 (MIM#619951)

This syndrome is due to monoallelic pathogenic variants in the H4C9 gene (MIM*602833). It is an autosomal dominant disorder; however, all variants occurred de novo. Affected individuals exhibit developmental delay, cognitive impairment, learning difficulties, behavioral disturbances (communication and social difficulties), growth failure, hypotonia, hearing impairment, ocular anomalies (decreased visual acuity and strabismus), microcephaly, skeletal deformities (craniosynostosis, kyphosis, scoliosis, finger camptodactyly, toes anomalies, and rocker-bottom feet), genitourinary anomalies (absent kidney, vesicoureteral reflux, micropenis, and cryptorchidism), gastrointestinal anomalies (feeding difficulties), and facial dysmorphisms (narrow forehead, preauricular pits, hypertelorism, short philtrum, down-slanted palpebral fissures, everted lower lip, and prominent or depressed nasal bridge) [98].

Disorders of histone modifications

Up to this point, 35 disorders have been identified for histone modifications. These include 24 disorders of histone methylation and demethylation (16 disorders of histone methylation and 8 disorders of histone demethylation) (Fig. 1 and Table 2); and 11 disorders of histone acetylation and deacetylation (8 disorders of histone acetylation and 3 disorders of histone deacetylation) (Fig. 2 and Table 2).

Fig. 1

Disorders of histone methylation and histone demethylation. A diagram presenting different syndromes associated with deficiencies of histone methyltransferases (left) and histone demethylases (right). NDD: neurodevelopmental disorder; IDD: intellectual developmental disorder

Fig. 2

Disorders of histone acetylation and histone deacetylation. A diagram presenting different syndromes associated with deficiencies of histone acetyltransferases (left) and histone deacetylases (right)

Kabuki syndrome

This neurodevelopmental disorder is genetically heterogeneous with an estimated frequency of 1 in 32,000 [99]. The syndrome occurs due to pathogenic variants in KMT2D causing Kabuki syndrome 1 or in KDM6A causing Kabuki syndrome 2. The etiology remains unknown in 20% of affected individuals and both syndromes are associated with variable phenotypes [100].

Kabuki syndrome 1 (MIM#147920)

About 75% of individuals with Kabuki syndrome 1 have monoallelic pathogenic variants in the KMT2D gene (MIM*602113). It is an autosomal dominant disorder and variants mainly occur de novo [101]. Affected individuals with Kabuki 1 present with developmental delay, cognitive impairment, behavioral disturbances (attention deficit hyperactivity disorder, anxiety, sleep disturbances, and self-harm), autistic features, seizures, hypotonia, postnatal growth failure, hearing impairment, ocular anomalies, and microcephaly. Other reported anomalies include cardiovascular malformations (septal defects and coarctation of the aorta), gastrointestinal anomalies (feeding difficulties, malabsorption, intestinal malrotation, anoperitoneal fistula, anal stenosis, and imperforate anus), genitourinary anomalies (small penis, cryptorchidism, fused kidneys, and ureteropelvic junction obstruction), endocrinologic anomalies (congenital hypothyroidism and premature thelarche), skeletal deformities (vertebral anomalies, scoliosis, congenital hip dislocation, joint hypermobility, short fifth finger, persistent fetal fingertip pads), respiratory anomalies (aspiration pneumonias), immunologic abnormalities (increased susceptibility to infections and recurrent otitis media), hematologic anomalies (immune thrombocytopenic purpura and hemolytic anemia), dermatological manifestations (café au lait spots and hirsutism), facial dysmorphisms (trapezoid philtrum, large prominent ears, posteriorly rotated ears, preauricular pits, arched and broad eyebrows, thick eyelashes, depressed nasal tip, short nasal columella, ptosis, eversion of the lateral third of the lower eyelids, long palpebral fissures, and cleft or high-arched palate) [102, 103].

Kabuki syndrome 2 (MIM#300867)

Approximately 5% of the reported cases have Kabuki syndrome 2 due to heterozygous or hemizygous pathogenic variants in the KDM6A gene (MIM*300128) and it is inherited in an X-linked dominant manner [104].

Individuals with Kabuki 2 syndrome may manifest in neonates with neonatal hypoglycemia and feeding problems. Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances, autistic features, growth failure, seizures, hypotonia, hearing loss, ocular anomalies (strabismus and nystagmus), microcephaly, cardiovascular malformations (septal defects, pulmonary valve stenosis, hypoplastic right ventricle, and coarctation of the aorta), genitourinary abnormalities (horseshoe kidney), endocrine disorders (hyperinsulinism), skeletal abnormalities (joint hyperlaxity, brachydactyly, and persistent fetal fingertip pads), facial dysmorphisms (prominent and cupped ears with large auricles, sparse lateral and arched eyebrows, long eyelashes, long palpebral fissures, everted lateral third of the lower eyelid, short columella, broad and depressed nasal tip, high arched or cleft palate, dental malocclusion, hypodontia, abnormal dentition, and neonatal teeth), and abnormal neuroimaging (ventriculomegaly and delayed myelination). Compared to females, males with Kabuki syndrome 2 had a higher frequency of severe cognitive impairment; were born earlier with shorter birth lengths; fewer males developed speech or could walk independently; and had a higher frequency of gastrointestinal problems [105].

Wiedemann–Steiner syndrome (MIM#605130)

This syndrome is due to monoallelic pathogenic variants in the KMT2A gene (MIM*159555). It is an autosomal dominant disease; however, almost all variants occurred de novo [106].

Affected individuals have developmental delay, cognitive impairment, behavioral disturbances (hyperactivity and aggressivity), autistic features, seizures, hypotonia, wide based gait, hearing impairment, ocular anomalies (strabismus, astigmatism, and blepharoptosis), growth failure (short stature and underweight), cardiovascular malformations (ventricular septal defects and patent ductus arteriosus), endocrinologic anomalies (premature thelarche), genitourinary anomalies (vesicoureteral reflux, hydronephrosis, absent uterus in females, and cryptorchidism), immunologic anomalies (recurrent infections and abnormal immunoglobulin levels), gastrointestinal anomalies (feeding difficulties and constipation), endocrine abnormalities (growth hormone deficiency, premature adrenarche, hypothyroidism, and hypoparathyroidism), respiratory anomalies (obstructive sleep apnea), skeletal deformities (fusion anomalies in cervical spine, clinodactyly, brachydactyly, fleshy hands and feet, tapering fingers, sacral dimple, tethered cord, spina bifida occulta), premature loss of deciduous teeth, hypertrichosis cubitis, facial dysmorphisms (flat face, long eyelashes, thick eyebrows, hypertelorism, narrow and down-slanted palpebral fissures, long philtrum, broad nose, wide nasal bridge, depressed nasal tip, dysmorphic and low-set ears, thin upper lip, high arched or cleft palate, and exaggerated cupid’s bow), and abnormal neuroimaging findings (abnormal corpus callosum, white matter changes, Chiari malformation, and periventricular nodular heterotopia) [107, 108].

Kleefstra syndrome

The incidence of this genetically heterogeneous syndrome is estimated to be 1:25,000 to 1:35,000. It is associated with variable phenotypes and occurs due to pathogenic variants in EHMT1 causing Kleefstra syndrome 1 and in KMT2C causing Kleefstra syndrome 2 [109].

Kleefstra syndrome 1 (MIM#610253)

This syndrome is due to monoallelic pathogenic variants in the EHMT1 gene (MIM*607001). It is an autosomal dominant disorder; however, almost all pathogenic variants occur de novo.

Affected individuals exhibit developmental delay, cognitive impairment, autistic features, behavioral disturbances (sleep disorders, stereotypic movements, aggressive behavior, self-injurious behavior, progressive apathy, and catatonic like behavior), psychiatric manifestations (obsessive–compulsive disorder), seizures, hypotonia, hearing impairment, ocular anomalies (hypermetropia), microcephaly, cardiovascular malformations (tetralogy of Fallot, septal defects, coarctation of the aorta, bicuspid aortic valve, atrial flutter, and pulmonic stenosis), skeletal deformities (kyphosis, scoliosis, brachydactyly, duplicated thumb, talipes equinovarus, and single transverse palmar crease), renal anomalies (vesicoureteral reflux, hydronephrosis, chronic renal insufficiency, and renal cysts), genital anomalies (hypospadias, cryptorchidism, and small penis), gastrointestinal anomalies (gastroesophageal reflux and epigastric hernias), respiratory anomalies (tracheobronchomalacia and respiratory insufficiency), obesity, and facial dysmorphisms (brachycephaly, flat face, midface hypoplasia, prognathism, coarse facies, malformed ears, thick ear helices, synophrys, hypertelorism, up-slanted palpebral fissures, anteverted nares, short nose, everted lower lip, cup-shaped mouth, and macroglossia) [110].

Kleefstra syndrome 2 (MIM#617768)

This syndrome is due to monoallelic pathogenic variants in the KMT2C gene (MIM*606833). It is inherited in an autosomal dominant pattern and usually presents as a milder phenotype. Most pathogenic variants occurred de novo. Affected individuals present with developmental delay, cognitive impairment, autistic features, behavioral disturbances (hyperactivity and aggressiveness), seizures, hypotonia, growth failure with short stature, microcephaly, skeletal deformities (scoliosis and kyphosis), distinctive facial features (midface hypoplasia, brachycephaly, coarse facies, thick ear helices, synophrys, arched and prominent eyebrows, hypertelorism, deep-set eyes, ptosis, high-arched palate, everted lower lip, and short nose), and abnormal neuroimaging (hypoplasia of the cerebellar vermis, hydrocephalus, and Dandy-Walker malformation) [105, 111].

Childhood-onset dystonia-28 (MIM#617284)

This syndrome is due to monoallelic pathogenic variants in the KMT2B gene (MIM*606834). Pathogenic variants inherited from affected or unaffected parents are consistent with an autosomal dominant pattern of inheritance with incomplete penetrance at around 85% penetrance [112]. Affected people exhibit early-onset progressive dystonia, usually in the first decade of life, and most pathogenic variants occur de novo [113].

Affected individuals have developmental delay, cognitive impairment, behavioral disturbances (attention deficit hyperactivity disorder), autistic features, and psychiatric manifestations (anxiety and depression). Early onset of lower limb dystonia manifesting as gait disturbances, toe walking, and foot posturing are the hallmarks of this syndrome. The dystonia is progressive and potentially becomes generalized to the upper extremities (dystonic tremor, decreased dexterity, and handwriting difficulties), the cervical area (torticollis and retrocollis), and the cranial nerves (facial dystonia, dysarthria, difficulty chewing, difficulty swallowing, and laryngeal involvement with dysarthria). Other common manifestations include pyramidal signs (spasticity and myoclonus), microcephaly, ocular anomalies (astigmatism, nystagmus, and slow saccades), growth failure with short stature, skeletal deformities (brachydactyly and clinodactyly), endocrinologic anomalies (precocious puberty), facial dysmorphisms (elongated face and bulbous nasal tip), and abnormal neuroimaging (signal abnormalities in globus pallidus) [114].

SETD1A-related disorders

Pathogenic variants in the SETD1A gene can cause two different syndromes: neurodevelopmental disorders with speech impairment and dysmorphic facies and early-onset epilepsy-2 with or without developmental delay.

Neurodevelopmental disorder with speech impairment and dysmorphic facies (MIM#619056)

This syndrome is due to monoallelic pathogenic variants in the SETD1A gene (MIM*611052). It is an autosomal dominant disorder; however, pathogenic variants occur de novo and it is associated with variable severity [115].

Affected people present with developmental delay, cognitive impairment, behavioral disturbances (short attention span, overfriendliness, sleep disturbances, and aggressive behavior), autistic features, psychiatric manifestations (anxiety, psychotic features, and schizophrenia), seizures, hypotonia, visual impairment, skeletal deformities (joint hypermobility, broad and long tapered fingers, and pes planus), gastrointestinal anomalies (feeding difficulties), recurrent infections, facial dysmorphisms (high forehead, full cheeks, widely spaced teeth, wide mouth, everted upper lip, low-set ears, microtia, down-slanted palpebral fissures, epicanthal folds, deep-set eyes, anteverted nares, and wide nose with broad tip), and abnormal neuroimaging (white matter changes and abnormal corpus callosum) [116].

Early-onset epilepsy-2 with or without developmental delay (MIM#618832)

This syndrome is due to monoallelic pathogenic variants in the SETD1A gene (MIM*611052). It is inherited in an autosomal dominant pattern. It is associated with variable severity and some pathogenic variants occur de novo. It is characterized by early-onset epilepsy (generalized tonic–clonic seizures) with or without developmental delay in the initial days, months, or years of life. Some individuals have poor growth, and abnormal neuroimaging (cerebral dysplasia, white matter abnormalities, delayed myelination, and enlarged ventricles) [117].

Intellectual developmental disorder with seizures and language delay (MIM#619000)

This syndrome is due to monoallelic pathogenic variants in the SETD1B gene (MIM*611055). It is inherited in an autosomal dominant pattern and most reported pathogenic variants occurred de novo with variable severity [117, 118].

Affected individuals present with developmental delay, cognitive impairment, seizures, behavioral disturbances (anxiety and attention deficit hyperactivity disorder), autistic features, ocular anomalies (eyelid myoclonus and fluttering), skeletal deformities (joint laxity, lumbar lordosis, tapering fingers, persistent fetal pads, and fifth finger clinodactyly), inguinal hernias, skin manifestations (pigmentary changes and eczema), and distinctive facial features (midface hypoplasia, smooth philtrum, full cheeks, small ears, thick eyebrows, short palpebral fissures, down-slanted or up-slanted palpebral fissures, sunken eyes, hypertelorism, proptosis, small nose, cleft lip and palate, thin upper lip, and oligodontia) [119, 120].

SETD2-related disorders

Pathogenic variants in the SETD2 gene can cause three different syndromes: Luscan-Lumish syndrome, Rabin–Pappas syndrome, and autosomal dominant intellectual developmental disorder 70.

Luscan-Lumish syndrome (MIM#616831)

This overgrowth syndrome is due to monoallelic pathogenic variants in the SETD2 gene (MIM*612778). It is inherited in an autosomal dominant with some variants occurring de novo [121].

Affected individuals present with developmental delay, cognitive impairment, behavioral disturbances (aggressiveness, temper tantrums, attention deficit hyperactivity disorder, high pain thresholds, self-injurious behavior, low sociability, shyness, hyperphagia, and behavioral outbursts), autistic features, psychiatric manifestations (anxiety and compulsions), seizures, hypotonia, macrocephaly, ocular anomalies (ptosis), hearing impairment, postnatal overgrowth, obesity, tall stature, endocrinologic anomalies (delayed bone age, polycystic ovaries syndrome, and menstrual irregularities), genitourinary anomalies (undescended testes), skeletal deformities (hyperlaxity of joints, and long or large hands and feet), dermatological manifestations (soft and elastic skin, nevus flammeus, and hirsutism), facial dysmorphisms (high frontal hairline, prominent forehead, malar hypoplasia, long face, down-slanted palpebral fissures, long nose, prominent mandible, tongue with deep creases, and pointed chin), and abnormal neuroimaging (ventriculomegaly, syringomyelia, and Chiari malformation) [122,123,124].

Rabin–Pappas syndrome (MIM#620155)

This syndrome is due to monoallelic pathogenic variants in the SETD2 gene (MIM*612778). It is an autosomal dominant disorder; however, all the variants occurred de novo [121].

Affected individuals have developmental delay, cognitive impairment, growth failure, seizures, hypotonia, hearing impairment, ocular anomalies (retinal telangiectasias, retinal exudates, retinal detachment, strabismus, cataracts, and optic nerve coloboma), microcephaly, cardiovascular malformations (septal defects, and aortic valve abnormalities), skeletal deformities (craniosynostosis, scoliosis, hip dysplasia, proximally implanted thumbs and halluces, hypoplasia of distal phalanges, camptodactyly, maxillary hypoplasia, mandibular hypoplasia, hypoplastic nails, and thoracic dysplasia), gastrointestinal anomalies (feeding difficulties), genitourinary anomalies (cryptorchidism, dilated collecting systems, and multicystic dysplastic kidneys), respiratory anomalies (hypoventilation, sleep apneas, and respiratory difficulties), recurrent infections, facial dysmorphisms (forward facing ears, small face, frontal bossing, micrognathia, hypertelorism, high arched eyebrows, short and up-slanted palpebral fissures, wide nasal bridge, broad nasal tip, upturned and small nose, and low hanging columella), and abnormal neuroimaging (shallow sulci, enlarged ventricles, hypoplasia of the pons, corpus callosum, and cerebellum) [121, 125].

Autosomal dominant intellectual developmental disorder-70 (MIM#620157)

This syndrome is due to monoallelic pathogenic variants in the SETD2 gene (MIM*612778). It is an autosomal dominant disorder; however, all variants occurred de novo [121]. Affected people exhibit developmental delay, cognitive impairment, psychiatric manifestations (anxiety), hypotonia, ocular anomalies (myopia and strabismus), skeletal deformities (malar flattening, joint hyperlaxity, camptodactyly, and fifth finger clinodactyly), endocrinologic anomalies (advanced bone age), gastrointestinal anomalies (constipation), respiratory manifestations (laryngomalacia), and facial dysmorphisms (prominent forehead, straight eyebrows, up-slanted palpebral fissures, broad nasal tip, high arched palate, crowded teeth, pointed chin, and retrognathia) [121, 122].

Rauch–Steindl syndrome (MIM#619695)

This syndrome is due to monoallelic pathogenic variants in the NSD2 gene (MIM*602952). It is inherited in an autosomal dominant pattern and associated with highly variable phenotypes. Most pathogenic variants were found to be de novo. Affected individuals have developmental delay, cognitive impairment, growth failure with short stature, behavioral anomalies (happy demeanor, hyperactivity, short attention span, and aggressive behavior), autistic features, psychiatric manifestations (anxiety), seizures, hypotonia, microcephaly, ocular anomalies (strabismus and refractive errors), skeletal deformities (pes planus and fifth finger clinodactyly), gastrointestinal anomalies (constipation and feeding difficulties), and facial dysmorphisms (craniofacial asymmetry, prominent forehead, high anterior hairline, triangular face, prominent glabella, low hairline, posteriorly rotated, prominent, and low-set ears, arched eyebrows, periorbital fullness, epicanthal folds, up-slanted palpebral fissures, deep-set eyes, flat and wide nasal bridge, bulbous nasal tip, short philtrum, microretrognathia, downturned corners of the mouth, thick lower lip, abnormal teeth, small chin, and long neck) [126, 127].

Sotos syndrome (MIM#117550)

This gigantism syndrome is due to monoallelic pathogenic variants in the NSD1 gene (MIM*606681). It is inherited in an autosomal dominant pattern with 95% of the pathogenic variants occurring de novo.

Based on a review done to address the symptoms of individuals affected with Sotos syndrome, the clinical features were classified as cardinal (in 90% or more of those affected), major (in 15–89%), and associated (in ≥ 2% and < 15% of affected) [128]. The cardinal features include developmental delay, cognitive impairment, overgrowth with macrocephaly, and distinctive facial features (sparse frontotemporal hair, dolichocephaly, down-slanted palpebral fissures, long narrow face, long chin, and malar flushing). Other reported facial dysmorphisms include hemihypertrophy, frontal bossing, prognathism, high-arched palate, teeth anomalies (premature tooth eruption, excessive tooth wear and crowding, enamel hypoplasia, and ectopic tooth eruption), hypoplastic nails, redundant skin folds, and skin hypo or hyperpigmentation. Major features include behavioral disturbances (phobias, aggression, and difficulty with peer group relationships), autistic features, seizures, cardiovascular malformations (patent ductus arteriosus, septal defects, aortic dilatation, and left ventricular non-compaction), skeletal deformities (advanced bone age, scoliosis, pes planus, and joints hyperlaxity), renal anomalies (vesicoureteral reflux and renal impairment), neonatal jaundice, hypotonia, poor feeding, and abnormal neuroimaging (corpus callosum hypoplasia or agenesis, ventricular dilatation, cavum septum pellucidum, mega cisterna magna, small cerebellar vermis, and cerebral atrophy). Associated features are many and include congenital hypotonia, lymphedema, hearing impairment, ocular anomalies (cataract, astigmatism, myopia, nystagmus, and strabismus), skeletal deformities (craniosynostosis, pectus excavatum, vertebral anomalies, umbilical hernia, toe syndactyly, talipes equinovarus, hypermobile joints, contractures, lymphedema nails, and abnormal fingertip dermatoglyphics), urogenital anomalies (renal agenesis with contralateral double kidney, cryptorchidism, hydrocele, phimosis, and hypospadias), gastrointestinal anomalies (gastroesophageal reflux, constipation, Hirschsprung disease, and polyps), endocrinologic anomalies (hypothyroidism and neonatal hypoglycemia), and neoplasia (neuroblastoma, sacrococcygeal teratoma, presacral ganglioma, small-cell lung cancer, acute lymphoblastic leukemia, and astrocytoma) [128,129,130].

Weaver syndrome (MIM#277590)

This overgrowth syndrome is due to monoallelic pathogenic variants in the EZH2 gene (MIM*601573). It is an autosomal dominant disorder; however, almost all variants occurred de novo [131].

Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances (phobias), autistic features, psychiatric manifestations (anxiety), overgrowth with advanced bone age and tall stature, seizures, hypertonia or hypotonia, spasticity, macrocephaly, hearing impairment, ocular anomalies (hypermetropia, myopia, and strabismus), cardiovascular malformations (patent ductus arteriosus, ventricular septal defect, and mitral valve prolapse), skeletal deformities (scoliosis, kyphosis, pectus excavatum or carinatum, short ribs, small iliac wings, coxa valga, large hands, broad thumbs, camptodactyly, prominent fingertip pads, clinodactyly, calcaneovalgus, talipes equinovarus, metatarsus adductus, pes cavus, short fourth metatarsals, overriding toes, ligamentous laxity, joint hypermobility, limited elbow and knee extension, and flared metaphyses), gastrointestinal anomalies (umbilical and hiatal hernia, poor feeding, gastroesophageal reflux, diastasis recti, and excessive appetite), genitourinary anomalies (cryptorchidism, hydrocele, and hypospadias), neoplasia (lymphoma, leukemia, neuroblastoma, and hemophagocytic lymphohistiocytosis), neonatal complications (hypoglycemia and hypocalcemia), skin manifestations (loose skin, increased pigmented nevi, thin hair, and palmar and plantar hyperhidrosis), dental dysplasia, serrated gums, low-pitched cry, facial dysmorphisms (almond-shaped palpebral fissures, large and fleshy ears, broad forehead, hypertelorism, stuck on appearance of chin, retrognathia, and deep-set nails) and abnormal neuroimaging (pachygyria, polymicrogyria, periventricular leukomalacia, absent septum pellucidum, and lateral ventriculomegaly) [132, 133] [131, 134].

Suleiman–El-Hattab syndrome (MIM#618950)

This syndrome is due to biallelic pathogenic variants in the TASP1 gene (MIM*608270) and is inherited in an autosomal recessive pattern. Affected children have developmental delay, behavioral disturbances (happy demeanor), growth failure with failure to thrive and short stature, seizures, hypotonia, microcephaly, unsteady gait, ocular anomalies (strabismus, amblyopia, hyperopia, and pale optic discs), hearing impairment, cardiovascular malformations (tetralogy of Fallot and septal defects), skeletal deformities (single palmar crease, clinodactyly, brachydactyly, and polydactyly), genitourinary anomalies (hydronephrosis and cryptorchidism), gastrointestinal anomalies (poor feeding and drooling), respiratory anomalies (respiratory insufficiency and recurrent respiratory infections), facial dysmorphisms (hirsutism, excessive forehead hair, preauricular skin tags, overfolded ear helices, low-set and prominent ears, arched and thick eyebrows, synophrys, prominent glabella, periorbital fullness, epicanthus, hypertelorism, thick eyelids, down-slanted palpebral fissures, broad nasal bridge, long smooth philtrum, microretrognathia, thin upper and thick lower lips, wide mouth, and webbed neck), and abnormal neuroimaging (enlarged posterior fossa, dilated fourth ventricle, cerebellar vermian hypoplasia, and Dandy-Walker malformation) [135, 136].

PROSER1-related neurodevelopmental syndrome

This neurodevelopmental syndrome is due to biallelic pathogenic variants in the PROSER1 gene (MIM*620773) and is inherited in an autosomal recessive pattern. Affected people exhibit developmental delay, autistic features, failure to thrive, seizures, hypotonia, ataxia, hearing impairment, ocular anomalies (strabismus, retinal and optical discs coloboma, and amblyopia), microcephaly, cardiovascular malformations (ventricular septal defect), respiratory anomalies (asthma, adenoid hypertrophy, and obstructive sleep apnea), gastrointestinal anomalies (drooling, feeding difficulties, and necrotizing enterocolitis), genitourinary anomalies (pelvic or hypoplastic kidney, ureteropelvic junction obstruction, hydronephrosis, and cryptorchism), skeletal deformities (pectus excavatum, joint hyperlaxity, and recurrent fractures), recurrent otitis media, prenatal anomalies (oligohydramnios, decreased fetal movements, and intrauterine growth restriction). They exhibit facial dysmorphisms such as parietal bossing, large and low-set ears, prominent eyes, arched eyebrows, broad nasal bridge, low-hanging columella, thick lower lip, open mouth, shortened tongue frenulum, and protruding tongue [137].

Cleft palate, psychomotor disability, and distinctive facial features (MIM#616728)

This syndrome is due to monoallelic pathogenic variants in the KDM1A gene (MIM*609132). It is an autosomal dominant disorder; however, all pathogenic variants occurred de novo [138, 139]. Affected people exhibit cleft palate, developmental delay, seizures, hypotonia, macrocephaly, ocular anomalies (strabismus and oculomotor apraxia), cardiovascular malformations (patent foramen ovale), skeletal deformities (tapered fingers, brachydactyly, clinodactyly, short thumbs, hypoplastic toenails, calcaneal valgus), genitourinary anomalies (chordae and hypospadias), facial dysmorphisms (brachycephaly, hypertrichosis, sparse temporal and eyebrow hair, high anterior hairline, prominent forehead, synophrys, hypertelorism, ptosis, blue sclerae, down-slanted palpebral fissures, widely spaced teeth, thin upper lip, broad nasal tip, conical canines, and supernumerary nipples), and abnormal neuroimaging (spinal stenosis, dysmorphic and thin corpus callosum, small cerebellum, white matter hypoplasia, delayed myelination, and prominent horns of the lateral ventricles) [138,139,140].

Diets–Jongmans syndrome (MIM#618846)

This syndrome is due to monoallelic pathogenic variants in the KDM3B gene (MIM*609373). It is an autosomal dominant disorder; however, almost all pathogenic variants occurred de novo. Affected people present with developmental delay, cognitive impairment, behavioral disturbances (delayed socioemotional development, aggressive behavior, and attention deficit hyperactivity disorder), autistic features, seizures, hypotonia, hearing impairment, ocular anomalies (ptosis, nystagmus, strabismus, and low vision), short stature, cardiovascular malformations (interrupted inferior vena cava and ventricular septal defect), gastrointestinal anomalies (feeding difficulties, umbilical and diaphragmatic hernias, and duodenal atresia), neoplasia (myeloid leukemia and Hodgkin’s lymphoma), skeletal deformities (hip dysplasia and joint hypermobility), genitourinary anomalies (inguinal hernias, hypospadias, and cryptorchidism), heterotaxia, and facial dysmorphisms (long ears, broad nasal tip, down-slanted or up-slanted palpebral fissures, low columella, thin upper vermillion, wide mouth, and pointed or prominent chin) [141].

El Hayek–Chahrour neurodevelopmental syndrome (MIM#620820)

This syndrome is due to biallelic pathogenic variants in the KDM5A gene (MIM*180202) and is inherited in an autosomal recessive pattern. Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances (sleep difficulties), autistic features, microcephaly, growth failure (short stature and failure to thrive) seizures, hypotonia, cardiovascular malformations (septal defects and coarctation of the aorta), gastrointestinal anomalies (feeding difficulties), skeletal deformities (toes syndactyly and clinodactyly), facial dysmorphisms (hypertelorism, down-slanted palpebral fissures, low-set ears, small philtrum, and micrognathia), and abnormal neuroimaging (hippocampal atrophy, periventricular leukomalacia, gliosis, and hypoplastic corpus callosum) [142].

Autosomal recessive intellectual developmental disorder-65 (MIM#618109)

This syndrome is due to biallelic pathogenic variants in the KDM5B gene (MIM*605393) and is inherited in an autosomal recessive pattern. Affected people present with developmental delay, cognitive impairment, behavioral disturbances (sleep disturbances and attention deficit hyperactivity disorder), unsteady gait, ocular anomalies (myopia, astigmatism, strabismus, and ptosis), macrocephaly, cardiovascular malformations (atrial septal defect), genitourinary anomalies (inguinal hernias, hypospadias, and cryptorchidism), gastrointestinal anomalies (feeding difficulties), skeletal deformities (camptodactyly and joint laxity), facial dysmorphisms (prominent metopic ridge, dysmorphic ears, square face, down-slanted palpebral fissures, high nasal bridge, smooth philtrum, bulbous nasal tip, low-hanging columella, thin lips, and supernumerary nipple), and abnormal neuroimaging (thin corpus callosum) [143, 144].

Claes–Jensen syndrome (MIM#300534)

This syndrome is due to pathogenic variants in the KDM5C gene (MIM*314690) and is inherited in an X-linked manner with variable phenotypes. Hemizygous males exhibit more severe phenotypes compared to heterozygous females. Affected individuals have cognitive impairment, behavioral disturbances (compulsive hyperphagia, aggression, indolence, restlessness, anxiousness, overfriendliness, low frustration tolerance, and outbursts), autistic features, seizures, slowly progressive spastic quadriplegia, gait abnormalities (shuffling), microcephaly or macrocephaly, ocular anomalies (strabismus, myopia, and hypermetropia), short stature, genitourinary anomalies (small penis, small testes, and cryptorchidism), endocrine anomalies (hypothyroidism, obesity, and primary amenorrhea), muscular atrophy, skeletal deformities (pectus excavatum, large hands, brachydactyly, short and thick distal phalanges, small feet, and club feet), and facial dysmorphisms (hypertrichosis, alopecia aerate, large ears, raised earlobes, round face, small forehead, facial hypotonia, small and deep-set eyes, small eyelashes, up-slanted palpebral fissures, maxillary hypoplasia, flat philtrum, micrognathia, prognathism, high and narrow palate, thin upper lip, scrotal tongue, and diastema) [145,146,147].

Stolerman neurodevelopmental syndrome (NEDSST) (MIM#618505)

This syndrome is due to monoallelic pathogenic variants in the KDM6B gene (MIM*611577). It is an autosomal dominant disorder with variable phenotypes; however, all the variants occurred de novo. Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances (attention deficit hyperactivity disorder), autistic features, hypotonia, seizures, ocular anomalies (strabismus), cardiovascular malformations (superior vena cava abnormalities), gastrointestinal anomalies (feeding difficulties and gastroesophageal reflux), genitourinary anomalies (cryptorchidism), respiratory manifestations (laryngomalacia), skeletal deformities (abnormal dentition, pectus excavatum, wide hands, thick fingers, clinodactyly, toe syndactyly, and joints hypermobility), dermatological manifestations (skin hyperpigmentation, café au lait spots, and hemangiomas), and facial dysmorphisms (dolichocephaly, coarse facies, large ears, round face, prominent forehead, telecanthus, epicanthal folds, full cheeks, prominent nose, broad and depressed nasal bridge, prognathism, thick lips, wide mouth, short webbed neck, hypoplastic nipples, and prominent abdomen) [148].

Siderius X-linked intellectual developmental disorder (MIM#300263)

This syndrome is due to pathogenic variants in the PHF8 gene (MIM#300560) and is inherited in an X-linked recessive pattern. Affected individuals have developmental delay, cognitive impairment, behavioral disturbances (aggressiveness, uncontrollable outbursts, and attention deficit hyperactivity disorder), autistic features, psychiatric manifestations (anxiety), seizures, hearing impairment, ocular anomalies (strabismus, myopia, hypermetropia, and astigmatism), microcephaly or macrocephaly, skeletal deformities (thoracic kyphosis, flat feet, long and thin toes, preaxial polydactyly, long, large, or thin hands, and long and thin fingers), genitourinary anomalies (cryptorchidism and retractile testes), distinctive facial features (hypertelorism, long face, low posterior hairline, synophrys, low-set and posteriorly rotated ears, broad nasal tip, retrognathia, high-arched or cleft lip and palate), and abnormal neuroimaging (cortical dysplasia, polymicrogyria, thin corpus callosum, and hypoplastic posterior fossa) [149].

Rubinstein–Taybi syndrome

This is a genetically heterogeneous disorder with an estimated incidence of 1:100,000 and 1:125,000. Around 50%-60% of the cases are caused by pathogenic variants in CREBBP resulting in Rubinstein–Taybi syndrome 1 and 10% of cases are due to pathogenic variants in EP300 resulting in Rubinstein–Taybi syndrome 2. Both are autosomal dominant disorders; however, most pathogenic variants occur de novo in both types. Both syndromes are associated with variable phenotypes. The molecular cause for approximately 30% of cases remains unknown [150].

Rubinstein–Taybi syndrome 1 (MIM#180849)

Rubinstein–Taybi syndrome 1 is due to monoallelic pathogenic variants in the CREBBP gene (MIM*600140). Affected individuals have developmental delay, cognitive impairment, behavioral disturbances (grimacing, attention deficit hyperactivity disorder, and labile mood), autistic features, failure to thrive, seizures, hypotonia, hyporeflexia, hearing impairment, ocular anomalies (nasolacrimal duct obstruction, ptosis, strabismus, coloboma, glaucoma, and cataracts), microcephaly, cardiovascular malformations (septal defects, patent ductus arteriosus, pulmonary hypertension, mitral valve regurgitation, bicuspid aortic valve, aortic coarctation, vascular rings, and capillary hemangiomas), skeletal deformities (delayed skeletal maturation, late closure of fontanelles, hypoplastic maxilla, sternal anomalies, joint hypermobility, patellar dislocations, slipped capital femoral epiphysis, large parietal foramina and foramen magnum, spina bifida occulta, scoliosis, flared and small iliac wings, broad thumbs with radial angulation, syndactyly, polydactyly, clinodactyly, persistent fetal fingertip pads, and pes planus), dental anomalies (dental crowding, crossbite, enamel hypoplasia and discoloration, talon cusps, and screwdriver permanent incisors), genitourinary anomalies (hypoplastic kidney, hypospadias, shawl scrotum, and cryptorchidism), recurrent respiratory infections, gastrointestinal anomalies (feeding difficulties, constipation, and megacolon), endocrine anomalies (premature thelarche and obesity), neoplasia (increased risk of leukemia, rhabdomyosarcoma, oligodendroglioma, medulloblastoma, neuroblastoma, and meningioma), dermatologic abnormalities (café au lait spots and keloids formation), facial dysmorphisms (grimacing smile, down-slanted palpebral fissures, single transverse palmar crease, plantar crease between first and second toes, hirsutism, low-set ears, low anterior hairline, large anterior fontanelles, frontal bossing, long eyelashes, thick and high arched eyebrows, epicanthal folds, deviated nasal septum, beaked nose, broad nasal bridge, and microretrognathia), and abnormal neuroimaging (agenesis of corpus callosum) [151,152,153,154].

Rubinstein–Taybi syndrome 2 (MIM#613684)

This syndrome is due to monoallelic pathogenic variants in the EP300 gene (MIM*602700). Affected individuals have developmental delay, cognitive impairment, behavioral disturbances (attention deficit hyperactivity disorder), autistic features, failure to thrive, seizures, hypotonia, ocular anomalies (myopia), microcephaly, skeletal deformities (broad thumbs, syndactyly, square distal fingertips, genu valgum, pes valgus, scoliosis, hypermobility and dislocation of elbows, and broad great toes), dental anomalies (dental malocclusion, overbite, and dental caries), gastrointestinal anomalies (intestinal malrotation and feeding difficulties), genitourinary anomalies (cryptorchidism), hair tuft on paravertebral area, and facial dysmorphisms (hirsutism, posterior auricular helix pits, thick and arched eyebrows, long eyelashes, down-slanted palpebral fissures, prominent and beaked nose, long columella, narrow and high arched palate, and microretrognathia) [155,156,157].

Menke–Hennekam syndrome

This syndrome is genetically heterogeneous. It occurs due to pathogenic variants in CREBBP causing Menke–Hennekam syndrome 1 or in EP300 causing Menke–Hennekam syndrome 2. Both are autosomal dominant disorders; however, most pathogenic variants occur de novo in both types.

Menke–Hennekam syndrome 1 (MIM#618332)

This syndrome is due to monoallelic pathogenic variants in the CREBBP gene (MIM*600140) and is inherited in an autosomal dominant pattern. Affected people exhibit developmental delay, cognitive impairment, seizures, behavioral disturbances (self-injurious behavior), autistic features, hearing impairment, ocular anomalies (ptosis, strabismus, and hyperopia), microcephaly, short stature, cardiovascular malformations (atrial septal defects), genitourinary anomalies (renal anomalies, cryptorchidism, and inguinal hernias), gastrointestinal anomalies (feeding problems, constipation, and malrotation), respiratory anomalies (recurrent upper respiratory infections), skeletal deformities (scoliosis, kyphosis, clinodactyly, ulnar deviation of fingers, overlapping toes, sandal gap, fibular deviation of distal halluces, and cutaneous syndactyly), facial dysmorphisms (sparce hair, low-set, protruding, or cupped ears, overfolded ear helices, prominent forehead, full cheeks, micrognathia, thick eyebrows, long eyelashes, telecanthus, short and up-slanted palpebral fissures, blepharophimosis, short nose, anteverted nares, depressed or narrow nasal bridge, short columella, long philtrum, thin upper lip, cupid bow lip, and high or cleft palate), and abnormal neuroimaging (white matter changes and hypoplasia or agenesis of corpus callosum) [158,159,160].

Menke–Hennekam syndrome 2 (MIM#618333)

This syndrome is due to monoallelic pathogenic variants in the EP300 gene (MIM*602700) and is inherited in an autosomal dominant pattern. Affected individuals have developmental delay, cognitive impairment, behavioral disturbances (insomnia, excessive sleep, attention deficit hyperactivity disorder, and no feeling of hunger), autistic features, hypotonia, hearing impairment, ocular anomalies (strabismus and hypermetropia), gastrointestinal anomalies (feeding difficulties, constipation, and duodenal ulcers), skeletal deformities (delayed bone age, joint laxity, fibular deviation of distal halluces, long fingers, cutaneous syndactyly, overlapping toes, and broad halluces), absent teeth, immunologic anomalies (low immunoglobulin levels and recurrent infections), and facial dysmorphisms (short ears, prominent forehead, short and up-slanted palpebral fissures, blepharophimosis, epicanthal folds, depressed or narrow nasal bridge, full cheeks, deep philtrum, thin upper lip, and sandal gap) [155, 158].

Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (MIM#619103)

This syndrome is due to monoallelic pathogenic variants in the KAT5 gene (MIM*601409). It is an autosomal dominant disorder; however, all variants occurred de novo. Affected individuals have developmental delay, regression, cognitive impairment, behavioral disturbances (sleep disturbances, stereotypies, and attention deficit hyperactivity disorder), autistic features, seizures, hypotonia, hearing loss, hyperacusis, ocular anomalies (myopia and strabismus), microcephaly, genitourinary anomalies (horseshoe kidney, cryptorchidism, vesicourethral reflux, cryptorchidism and hypospadias), gastrointestinal anomalies (feeding difficulties, dysphagia, gastroesophageal reflux, and constipation), endocrinologic anomalies (growth hormone deficiency), skeletal deformities (clinodactyly and brachydactyly), facial dysmorphisms (round face, flat facial profile, almond shaped eyes, epicanthal folds, low-set ears, upturned and bulbous nose, depressed nasal bridge, down-slanted corners of the mouth, thick lower lip, cleft lip and palate, high arched palate, prognathism, and single palmar crease), and abnormal neuroimaging (thin and dysgenesis of corpus callosum, progressive cerebellar atrophy, polymicrogyria, and small anterior pituitary gland) [161].

Arboleda–Tham syndrome (MIM# 616268)

This syndrome is due to monoallelic pathogenic variants in the KAT6A gene (MIM*601408). It is an autosomal dominant disorder; however, all pathogenic variants occurred de novo [162, 163].

Affected individuals have developmental delay, cognitive impairment, autistic features, behavioral disturbances (sleep problems and stereotypies), psychiatric manifestations (obsessive–compulsive disorder), and seizures [164]. Additional manifestations include truncal hypotonia, axial hypertonia, dystonia, microcephaly, ocular anomalies (strabismus, ptosis, cortical visual impairment, and optic nerve atrophy), cardiovascular malformations (septal defects, patent ductus arteriosus, mitral valve prolapse with regurgitation, and patent foramen ovale), skeletal deformities (craniosynostosis, plagiocephaly, and dental anomalies), respiratory manifestations (respiratory distress and chronic lung disease), gastrointestinal anomalies (feeding difficulties, gastrointestinal reflux, constipation, and intestinal malrotation), genitourinary anomalies (cryptorchidism), facial dysmorphisms (low-set and posteriorly rotated ears, bitemporal narrowing, epicanthal folds, prominent nasal bridge and nasal root, microretrognathia, downturned corners of the mouth, thin and tented upper lip, and cleft lip), and abnormal neuroimaging (absence of olfactory bulb) [164,165,166,167].

KAT6B-related disorders

Pathogenic variants in the KAT6B gene can cause two different syndromes: Genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS).

Genitopatellar syndrome (MIM#606170)

This syndrome is due to monoallelic pathogenic variants in the KAT6B gene (MIM*605880) and is inherited in an autosomal dominant pattern. Most pathogenic variants occurred de novo [168].

Affected people exhibit developmental delay, cognitive impairment, hypotonia, hearing impairment, microcephaly, short stature, cardiovascular malformations (septal defects and patent ductus arteriosus), respiratory anomalies (laryngomalacia and pulmonary hypoplasia), genitourinary anomalies (hydronephrosis, multicystic kidneys, fused ectopic kidneys, hypospadias, micropenis, cryptorchidism, scrotal hypoplasia, hypoplastic perineum, clitoral hypotrophy or hypertrophy, and prominent or underdeveloped labia minora), gastrointestinal anomalies (tongue thrusting, poor swallowing, gastroesophageal reflux, and anus displaced anteriorly), endocrine anomalies (primary hypothyroidism and delayed puberty), skeletal deformities (osteoporosis, kyphoscoliosis, radioulnar synostosis, missing ribs, brachydactyly, hypoplasia of the ischia, absent patellae, dimple overlying the knees, clubfeet, flexion deformities of hips and knees, and delayed tooth eruption), facial dysmorphisms (sparse scalp hair, coarse facies, bitemporal narrowing, up-slanted palpebral fissure, prominent nose, short columella, high or flat nasal bridge, full cheeks, micrognathia, and downturned mouth corners), and abnormal neuroimaging (corpus callosum agenesis, ventriculomegaly, colpocephaly, and heterotopia) [169,170,171,172,173].

Say-Barber-Biesecker-Young-Simpson syndrome (MIM#603736)

This syndrome is due to monoallelic pathogenic variants in KAT6B and is inherited in an autosomal dominant pattern. Most pathogenic variants occurred de novo [168].

Affected people exhibit developmental delay, cognitive impairment, hypotonia, feeding difficulties, microcephaly, ocular anomalies (myopia, amblyopia, ptosis, lacrimal duct abnormalities, and macular degeneration), cardiovascular malformations (septal defects and patent foramen ovale), genitourinary anomalies (cryptorchidism), skeletal deformities (torticollis, pectus chest deformity, displaced and hypoplastic patellae, great toes and long thumbs, clinodactyly, and talipes equinovarus), dental anomalies (retained primary dentition, natal teeth, and delayed teeth eruption), endocrine anomalies (hypothyroidism and thyroid agenesis or hypoplasia), facial dysmorphisms (myopathic mask facies, prominent occiput, posteriorly angulated and low-set ears, blepharophimosis, ptosis, epicanthus inversus, flat nasal bridge, bulbous nose, prominent cheeks, micrognathia, and orofacial cleft), and abnormal neuroimaging (white matter abnormalities) [174, 175].

Neurodevelopmental disorder with central hypotonia and dysmorphic facies (MIM#619797)

This syndrome is due to monoallelic pathogenic variants in the HDAC4 gene (MIM*605314). It is an autosomal dominant disorder; however, all pathogenic variants occurred de novo [176].

Affected individuals have developmental delay, cognitive impairment, behavioral disturbances (sleeping difficulties), seizures, hypotonia, ocular anomalies (absence of tracking, astigmatism, hypermetropia, hyperopia, esotropia, and amblyopia), cardiovascular malformations (patent ductus arteriosus), respiratory anomalies (apneas), gastrointestinal anomalies (feeding and swallowing difficulties), genitourinary anomalies (hydronephrosis and cryptorchidism), skeletal deformities (delayed fontanel closure, kyphosis, scoliosis, hip subluxation or dislocation, hyperextensible finger joints, asymmetric chest wall, pectus carinatum, talipes equinovarus, and delayed dentition), hyperpigmented macules, facial dysmorphisms (large ears, frontal hair upsweep, hypertelorism, long palpebral fissures, full lower lip, widely spaced teeth, and drooling), and abnormal neuroimaging (ventriculomegaly, thin corpus callosum, and cerebellar, cerebral, and brainstem atrophy) [176].

Chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia (MIM#300863)

This syndrome is due to pathogenic variants in the HDAC6 gene (MIM*300272) and is inherited in an X-linked dominant pattern. Affected individuals have cognitive impairment, growth failure with short stature, hydrocephaly, macrocephaly, ocular anomalies (microphthalmia), skeletal deformities (short ribs, severe platyspondyly, thick intervertebral disks, rhizomelia, and endochondral, diaphyseal, and endomembranous ossification, poor mineralization of skull, missing ribs, iliac wings hypoplasia, and metatarsals, metacarpals, and phalanges metaphyseal cupping), and facial dysmorphisms (low-set ears, frontal bossing, and short and flat nose). Affected females typically show a milder phenotype [177, 178].

Cornelia de Lange syndrome 5 (MIM#300882)

This syndrome is due to pathogenic variants in the HDAC8 gene (MIM*300269) and is inherited in an X-linked dominant pattern with variable severity. It accounts for 4% of people diagnosed with Cornelia de Lange syndrome [179].

Affected individuals have cognitive impairment, behavioral disturbances (happy demeanor), growth failure with short stature, hypotonia, hearing impairment, ocular anomalies (myopia), microcephaly, skeletal deformities (small hands and feet, metacarpal anomalies, delayed closure of fontanelles, toes syndactyly, and valgus deformity), genitourinary anomalies (impaired renal function, posterior urethral valves, recurrent urinary infections, small penis and testes, and cryptorchidism), endocrinologic anomalies (hypogonadism and truncal obesity), gastrointestinal anomalies (gastroesophageal reflux and feeding difficulties), dermatologic manifestations (hirsutism, nevus flammeus, and cutis marmorata), and facial dysmorphisms (brachycephaly, low anterior hairline, synophrys, deep-set eyes, arched eyebrows, hypertelorism, telecanthus, ptosis, hooding of upper eyelids, long eyelashes, bulbous nasal tip, depressed nasal bridge, anteverted nares, long philtrum, long columella, microretrognathia, downturned mouth borders, cleft lip and palate, and widely spaced teeth). Females can be mildly affected or unaffected [180,181,182].

Disorders of chromatin remodeling

To date, 26 disorders of chromatin remodeling have been described including 8 syndromes related to defects in chromatin organization (CHD remodelers), 16 syndromes related to defects in chromatin access (SWI/SNF remodelers), and 2 syndromes related to defects in chromatin editing (INO80 remodelers) (Fig. 3 and Table 2).

Fig. 3

Disorders of chromatin remodeling. A diagram presenting syndromes associated with defects in chromatin organization (CHD remodelers) (top left), syndromes associated with defects in chromatin access (SWI/SNF remodelers) (right), and syndromes associated with defects in chromatin editing (INO80 remodelers) (bottom left)

Pilarowski–Bjornsson syndrome (MIM#617682)

This neurodevelopmental disorder is caused by monoallelic pathogenic variants in the CHD1 gene (MIM*602118). It is inherited in an autosomal dominant pattern with variable phenotypes. Most pathogenic variants occur de novo. Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances (stereotypies), autistic features, growth failure, hypotonia, seizures, macrocephaly, immunologic disorders (immunodeficiency and allergic manifestations), and facial dysmorphisms (frontal bossing, depressed midface, pointed chin, flared eyebrow, periorbital fullness, almond-shaped eyes, down-slanted palpebral fissures, and translucent skin) [183].

Developmental and epileptic encephalopathy 94 (MIM#615369)

This syndrome is due to monoallelic pathogenic variants in the CHD2 gene (MIM*602119) and is inherited in an autosomal dominant pattern. Some variants occurred de novo. Affected people exhibit developmental delay, regression (after seizures onset), cognitive impairment, behavioral disturbances (attention deficit hyperactivity disorder), and autistic features. Almost all affected individuals develop multiple seizure types. The seizures are usually resistant to therapy [140, 184, 185].

Snijders Blok-Campeau syndrome (MIM#618205)

This neurodevelopmental syndrome is due to monoallelic pathogenic variants in the CHD3 gene (MIM*602120) and is inherited in an autosomal dominant manner with variable severity. Most variants occur de novo [186]. Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances (stereotypies and friendliness), autistic features, seizures, hypotonia, broad-based and unsteady gait, dysarthria, macrocephaly, ocular anomalies (hypermetropia, astigmatism, strabismus, and cerebral visual impairment), inguinal and umbilical hernia, skeletal deformities (joint hyperlaxity and foot deformities), cardiovascular malformations (septal defects and patent ductus arteriosus), facial dysmorphisms (high, broad, or prominent forehead, midface hypoplasia, full cheeks, low-set ears, laterally sparse eyebrows, hypertelorism, epicanthal folds, deep-set eyes, broad nasal bridge, high-arched palate, thin upper lip, absent teeth namely lateral incisors, and pointed chin), and abnormal neuroimaging (enlarged ventricles, delayed myelination, prominent extra-axial spaces, cerebral dysgenesis, and short corpus callosum) [187].

Sifrim–Hitz-Weiss syndrome (MIM#617159)

This syndrome is due to monoallelic pathogenic variants in the CHD4 gene (MIM*603277). It is inherited in an autosomal dominant pattern with variable phenotypes and most variants occur de novo. Affected people exhibit developmental delay, cognitive impairment, hypotonia, hearing impairment, ocular anomalies (astigmatism), macrocephaly, cardiovascular malformations (aortic coarctation, tetralogy of Fallot, septal defects, congenital stroke, hypertension, and moyamoya disease), skeletal deformities (Wormian bones, basal skull abnormalities, cervical fusion, fusion of wrist and foot bones, broad and short clavicles, short femoral neck, flat acetabular roof, tapered fingers, and post-axial polydactyly), genitourinary anomalies (renal insufficiency, vesicoureteral reflux, micropenis, cryptorchidism, and ambiguous genitalia), endocrinologic anomalies (hypogonadotropic hypogonadism in males), gastrointestinal anomalies (omphalocele and anteriorly placed anus), facial dysmorphisms (trigonocephaly, coarse facies, low-set, cupped, or abnormally shaped ears, ptosis, hypertelorism, epicanthal folds, short and up-slanted palpebral fissures, and palatal abnormalities), and abnormal neuroimaging (enlarged ventricles, and Chiari malformation) [188,189,190].

Parenti-Mignot neurodevelopmental syndrome (MIM#619873)

This neurodevelopmental disorder is due to monoallelic pathogenic variants in the CHD5 gene (MIM*610771). It is inherited in an autosomal dominant pattern with variable severity and most variants occur de novo. Affected individuals present with developmental delay, cognitive impairment, behavioral disturbances (anger, aggression, and self-injurious behavior), autistic features, psychiatric manifestations (obsessive–compulsive disorder), growth failure, seizures, ataxic gait, hypotonia, skeletal deformities (craniosynostosis and scoliosis), and facial dysmorphisms (high forehead, frontal bossing, epicanthal folds, up-slanted palpebral fissures, low-set and posteriorly rotated ears, and prominent nasal bridge) [191].

CHD7-related disorders

Pathogenic variants in the CHD7 gene can cause two different syndromes: CHARGE syndrome and hypogonadotropic hypogonadism 5 with or without anosmia.

CHARGE syndrome (MIM#214800)

This syndrome is due to monoallelic pathogenic variants in the CHD7 gene (MIM*608892) and is inherited in an autosomal dominant pattern with highly variable phenotypes. Most variants occur de novo and its estimated prevalence is 1 in 10,000 births. It is an acronym for coloboma, heart malformations, atresia of the choanae, retarded mental development and growth, genital anomalies, ear malformations, and hearing loss [192].

Developmental delay is a common symptom. Affected individuals can also have cognitive impairment, although 50% of individuals are in the normal intellectual range. Many adults with CHARGE syndrome can live independently and attain college or advanced degrees [193, 194]. Reported behavioral disturbances include attention deficit hyperactivity disorder, repetitive behavior, and increased pain threshold. They also have autistic features, psychiatric manifestations (obsessive–compulsive disorder and anxiety), growth failure, seizures, cranial nerves dysfunctions (hyposmia or anosmia, facial palsy, sensorineural hearing loss, difficulties with suck and swallow, and gastrointestinal dysmotility), vestibular dysfunction (imbalance), hypotonia, microcephaly, ear malformations (ossicular malformations, Mondini defect, and semicircular canal defect), and ocular anomalies (ocular coloboma, refractive errors, loss of central or upper visual field, light sensitivity, retinal detachment, and vision loss). Other findings include cardiovascular malformations (tetralogy of Fallot, septal defects, patent foramen ovale, double outlet right ventricle, pulmonary valve stenosis, patent ductus arteriosus, vascular sling, and aberrant aortic artery), skeletal deformities (craniosynostosis, scoliosis, vertebral anomalies, missing or extra ribs, absent long bones, polydactyly, ectrodactyly, brachydactyly, finger-like thumb, hypermobility, and contractures), dental anomalies (overbite, hypodontia, and poor mineralization of teeth), gastrointestinal anomalies (esophageal atresia, tracheoesophageal fistula, gastroesophageal reflux, duodenal or anal atresia, constipation, abdominal pain, feeding difficulties, intussusception, intestinal malrotation, umbilical hernia, and omphalocele), respiratory anomalies (laryngotracheomalacia), genitourinary anomalies (vesicoureteral reflux, missing, ectopic, cystic, hypoplastic, or horseshoe kidneys, hydronephrosis, micropenis, cryptorchidism, and small labia), endocrinologic anomalies (hypogonadotropic hypogonadism, uterine abnormalities, delayed or absent puberty, infertility, growth hormone deficiency, hypothyroidism, and parathyroid hypoplasia), hypocalcemia, and immune dysfunction (absent thymus, decreased number or function of T cells, and recurrent upper airway infections). The distinctive features are mainly related to external ear anomalies and include short, cupped, or asymmetrical pinnae, distinctive triangular concha, helical folds with snipped-off portions, and discontinuity between antitragus and antihelix. Other common facial dysmorphisms include a square face, malar flattening, facial asymmetry, microphthalmia, anophthalmia, hypertelorism, down-slanted palpebral fissures, anteverted nares, cleft lip, and cleft palate. In addition, individuals with CHARGE syndrome may have abnormalities in neuroimaging including hypoplastic or J-shaped sella, clivus hypoplasia, Dandy-Walker malformation, ventriculomegaly, and hypoplasia of the cerebellar vermis, corpus callosum, brainstem, or frontal lobe) [195,196,197,198,199,200].

Hypogonadotropic hypogonadism 5 with or without anosmia (MIM#612370)

This syndrome is due to monoallelic pathogenic variants in the CHD7 gene (MIM*608892) and is inherited in an autosomal dominant pattern. Some variants occur de novo. Affected individuals present with hypogonadotropic hypogonadism which results in absent or incomplete sexual maturation, and genitourinary anomalies (micropenis, cryptorchidism, and amenorrhea). Other reported anomalies include hearing impairment, and skeletal deformities (cleft lip and palate). Some affected individuals have an impaired sense of smell (anosmia) [201].

Intellectual developmental disorder with autism and macrocephaly (MIM#615,032)

This syndrome is due to monoallelic pathogenic variants in the CHD8 gene (MIM*610,528) and is inherited in an autosomal dominant pattern. Most pathogenic variants occurred de novo. Affected people exhibit regression and developmental delay, cognitive impairment, behavioral disturbances (sleep disturbances, attention deficit hyperactivity disorder, aggression, and self-injury), autistic features, psychiatric manifestations (anxiety and psychosis), seizures, hypotonia, macrocephaly, tall stature, gastrointestinal anomalies (constipation), skeletal deformities (pes planus and scoliosis), facial dysmorphisms (glabellar hemangioma, large ears, posteriorly rotated ears with fleshy lobes, prominent supraorbital ridge, down-slanted palpebral fissures, hypertelorism, long philtrum, broad nasal bridge, fleshy lips, and cupid bow mouth), and abnormal neuroimaging (ventriculomegaly, delayed myelination, and widened cranial vault) [202,203,204].

Coffin–Siris syndrome

This is a genetically heterogeneous syndrome inherited in an autosomal dominant pattern. The syndromes are associated with variable phenotypes and most variants occur de novo in all types. Molecular confirmation of Coffin–Siris syndrome has been reported in less than 200 people. It occurs due to pathogenic variants in ARID1B causing Coffin–Siris syndrome 1, in ARID1A causing Coffin–Siris syndrome 2, in SMARCB1 causing Coffin–Siris syndrome 3, in SMARCA4 causing Coffin–Siris syndrome 4, in SMARCE1 causing Coffin–Siris syndrome 5, in ARID2 causing Coffin–Siris syndrome 6, in DPF2 causing Coffin–Siris syndrome 7, in SMARCC2 causing Coffin–Siris syndrome 8, in SMARCD1 causing Coffin–Siris syndrome 11, or in BICRA causing Coffin–Siris syndrome 12 [205, 206].

Coffin–Siris syndrome 1 (MIM#135900)

Coffin–Siris syndrome 1 is due to monoallelic pathogenic variants in the ARID1B gene (MIM*614556). Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances (withdrawal, attention deficit hyperactivity disorder, shyness, friendly, and aggressive), autistic features, psychiatric manifestations (obsessive–compulsive disorder), seizures, hypotonia, ocular anomalies (visual impairment, strabismus, and myopia), skeletal deformities (prominent finger pads, interphalangeal joints, and distal phalanges, single transverse palmar crease, hypoplastic or absent terminal phalanges of 5th fingers and toes, hypoplastic or aplastic nails, and hip dislocations), delayed dentition, cardiovascular malformations (patent ductus arteriosus, aortic coarctation, ventricular septal defect, and patent foramen ovale), recurrent respiratory infections, gastrointestinal anomalies (feeding difficulties), distinctive features (hoarse or high pitched voice, simple, posteriorly rotated and low-set ears, sparse scalp hair, facial and lumbosacral hypertrichosis, low anterior hairline, long lashes, bushy and arched eyebrows, down-slanted palpebral fissures, short philtrum, broad nasal tip with columella below alae nasi, large mouth, thin upper lip and thick lower lip, small chin, and lower lip droop), hyperkeratotic plaques, and abnormal neuroimaging (corpus callosum hypoplasia or agenesis, hippocampal malrotation, and choroidal cysts) [205, 207, 208].

Coffin–Siris syndrome 2 (MIM#614607)

This syndrome is due to monoallelic pathogenic variants in the ARID1A gene (MIM*603024). Affected individuals exhibit developmental delay, cognitive impairment, behavioral disturbances (hyperactivity), seizures, hypotonia, ocular anomalies (visual impairment and strabismus), skeletal deformities (delayed bone age, brachydactyly, hypoplastic or absent terminal phalanges in 5th fingers and toes, hypoplastic nails), and delayed dentition, inguinal hernias, cardiovascular malformations (septal defects, aortic coarctation, and atrioventricular block), gastrointestinal anomalies (feeding problems, pyloric stenosis, gastroesophageal reflux, anal atresia, intestinal obstruction, and Hirschsprung disease), genitourinary anomalies (hypospadias and cryptorchidism), facial dysmorphisms (low anterior hairline, hypertrichosis, sparse scalp hair, coarse facial features, ear malformations, long eyelashes, thick eyebrows, broad nose, anteverted nostrils, thick alae nasi, flat nasal bridge, large mouth, macroglossia, thin upper lip, and thick lower lip), and abnormal neuroimaging (corpus callosum agenesis or malformation) [205, 207, 209, 210].

Coffin–Siris syndrome 3 (MIM#614608)

This syndrome is due to monoallelic pathogenic variants in the SMARCB1 gene (MIM*601607). Affected people present with developmental delay, cognitive impairment, behavioral disturbances (hyperactivity), growth failure (intrauterine growth restriction and short stature), seizures, hypotonia, hearing impairment, ocular abnormalities (absent or nonfunctioning tear duct and visual impairment), microcephaly, cardiovascular malformations (septal defects, pulmonic stenosis, and dextrocardia), skeletal deformities (absent or hypoplastic nails, delayed bone age, scoliosis, hypoplastic or absent terminal phalanges 5th fingers and toes, and spinal anomalies), and delayed dentition. Hiatal, inguinal, umbilical, and diaphragmatic hernias, gastrointestinal anomalies (feeding difficulties, pyloric stenosis, gastroesophageal reflux, constipation, and duodenal ulcer), genitourinary anomalies (cryptorchidism, vesicoureteral reflux, hydroureter, hydronephrosis, horseshoe kidney, and vesical diverticulum), facial dysmorphisms (hirsutism, coarse facies, long eyelashes, thick eyebrows, abnormal ears, flat nasal bridge, broad nose, anteverted nostrils, large mouth, macroglossia, high palate, and thin upper and thick lower lips), and abnormal neuroimaging (small cerebellum, and absent corpus callosum) [205, 209, 210].

Coffin–Siris syndrome 4 (MIM#614609)

This syndrome is due to monoallelic pathogenic variants in the SMARCA4 gene (MIM*603254). Affected individuals have developmental delay, cognitive impairment, growth failure (intrauterine growth restriction and short stature), hypotonia, hearing impairment, ocular anomalies (visual impairment), microcephaly, cardiovascular malformations (atrioventricular septal defects), skeletal deformities (delayed bone age, scoliosis, hypoplastic or absent terminal phalanges 5th fingers and toes, and hypoplastic or absent nails), delayed dentition, inguinal hernias, gastrointestinal anomalies (pyloric stenosis, gastroesophageal reflux, constipation, gastric outlet syndrome, and feeding difficulties), genitourinary anomalies (calyceal fullness and cryptorchidism), facial dysmorphisms (hirsutism, sparse scalp hair, coarse facies, long eyelashes, thick eyebrows, flat nasal bridge, broad nose, anteverted nostrils, thick alae nasi, macroglossia, thin upper and thick lower lips, and large mouth), and abnormal neuroimaging (Dandy-Walker malformation and corpus callosum abnormalities) [209, 210].

Coffin–Siris syndrome 5 (MIM#614609)

This syndrome is due to monoallelic pathogenic variants in the SMARCE1 gene (MIM*603111). Affected individuals exhibit developmental delay, cognitive impairment, growth failure, seizures, microcephaly, cardiovascular malformations (atrial septal defects, aortic, tricuspid, or mitral stenosis, enlarged right ventricle, pulmonary hypertension, dextrocardia, cervical arterial anomalies, and atrioventricular block), skeletal deformities (long slender fingers, hypoplasia of distal phalanges, and hypoplastic or dysplastic toenails), gastrointestinal anomalies (pyloric stenosis and feeding difficulties), facial dysmorphisms (coarse facies, abnormal ears, sparse scalp hair, low anterior hairline, long eyelashes, thick eyebrows, flat nasal bridge, broad nose, thick anteverted alae nasi, thin upper and thick lower lips and large mouth), and abnormal neuroimaging (Dandy-Walker malformation, small cerebellum, and abnormal corpus callosum) [205, 209, 210].

Coffin–Siris syndrome 6 (MIM#617808)

This syndrome is due to monoallelic pathogenic variants in the ARID2 gene (MIM*609539). Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances (tics, repetitive behaviors, attention deficit hyperactivity disorder, aggressiveness, and sensitivity to loud sounds and certain food textures), psychiatric manifestations (anxiety and obsessions), seizures, hearing impairment, growth failure (intrauterine growth restriction and short stature), cardiovascular malformations (atrial septal defect), gastrointestinal anomalies (constipation and gastroesophageal reflux), skeletal deformities (plagiocephaly, Wormian bones, pectus excavatum, kyphoscoliosis, clinodactyly, brachydactyly, 5th finger brachymesophalangia, hypoplastic 5th fingers and toenails, clubfeet, and hip dysplasia), delayed dentition, yellow–brown teeth, diaphragmatic eventration, inguinal hernias, genitourinary anomalies (testicular torsion), facial dysmorphisms (mid-face hypoplasia, coarse facies, low-set ears, large or tall forehead, narrow and down-slanted palpebral fissures, epicanthal folds, broad nasal tip, flat nasal bridge, anteverted alae nasi, short and prominent philtrum, prominent nasolabial folds, thin upper and thick lower lips, microretrognathia, high arched or cleft palate, and single palmar crease), and abnormal neuroimaging (periventricular leukomalacia, prominent lateral ventricles, Dandy-Walker malformation, thin corpus callosum, and arachnoid cyst) [211,212,213].

Coffin–Siris syndrome 7 (MIM#618027)

This syndrome is due to monoallelic pathogenic variants in the DPF2 gene (MIM*601671). Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances (obsessive–compulsive behavior, hyperactivity, temper tantrums, and stereotypic movements), growth failure with short stature, hypotonia, hearing impairment, ocular anomalies (strabismus and hypermetropia), cardiovascular malformations (patent foramen ovale, valvular abnormalities, and septal defects), skeletal deformities (trigonocephaly, sagittal craniosynostosis, brachydactyly, clinodactyly, and hypoplastic nails), dental abnormalities (microdontia and delayed dentition), gastrointestinal anomalies (poor feeding and constipation), immunologic abnormalities (recurrent otitis media), facial dysmorphisms (coarse facial features, large, posteriorly rotated and low-set ears, sparse scalp hair, prominent forehead, down-slanted palpebral fissures, hypertelorism, thick eyebrows, depressed nasal bridge, thick or small alae nasi, thin upper and thick lower lips, and wide mouth), and abnormal neuroimaging (Chiari malformation, cerebellar atrophy, and small pituitary gland) [214].

Coffin–Siris syndrome 8 (MIM#618362)

This syndrome is due to monoallelic pathogenic variants in the SMARCC2 gene (MIM*601734). Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances (aggression, hypersensitivity to touch, self-injurious behavior, obsessive and rigid behavior, hyperactivity, and sleep disturbances), growth failure with short stature, seizures, hypotonia, spasticity, hydrocephalus, ocular anomalies (ptosis), skeletal deformities (scoliosis and kyphosis), gastrointestinal anomalies (feeding difficulties), dermatologic manifestations (vitiligo and café au lait macules), facial dysmorphisms (hypertrichosis, thin or thick scalp hair, prominent supraorbital ridges, thick eyebrows, upturned nose, anteverted nostrils, thin upper and thick lower lips), and abnormal neuroimaging (hydrocephalus, white matter loss, generalized cerebral atrophy, hypomyelination, and thinning of the corpus callosum) [215, 216].

Coffin–Siris syndrome 11 (MIM#618779)

This syndrome is due to monoallelic pathogenic variants in the SMARCD1 gene (MIM*601735). Affected people exhibit developmental delay, cognitive delay, hypotonia, ocular anomalies (astigmatism, nystagmus, divergent squint, and visual impairment), skeletal deformities (small hands and feet, short and slender fingers, and hypoplasia of fifth toenail), dentition anomalies, gastrointestinal anomalies (feeding difficulties and gastroesophageal reflux), genitourinary anomalies (cryptorchidism), prenatal anomalies (intrauterine growth restriction, and decreased fetal movements), facial dysmorphisms (sparse hair, low anterior hairline, myopathic facies, broad square face, temporal narrowing, dysplastic and low-set ears, hypertelorism, short nose, prominent philtrum, flat nasal bridge, wide mouth with downturned corners, and thick gums), and abnormal neuroimaging (corpus callosum agenesis) [217].

Coffin–Siris syndrome 12 (MIM#619325)

This syndrome is due to monoallelic pathogenic variants in the BICRA gene (MIM*605690). Affected people present with developmental delay, developmental regression, cognitive impairment, behavioral disturbances (motor stereotypies and sleep disturbances), autistic features, growth failure, seizures, hypotonia, hydrocephalus, hearing impairment, ocular anomalies (myopia, amblyopia, strabismus, and hyperopia), microcephaly or macrocephaly, cardiovascular malformations (tetralogy of Fallot and patent foramen ovale), gastrointestinal anomalies (celiac disease, gastroesophageal reflux, constipation, and feeding difficulties), genitourinary anomalies (hypospadias, cryptorchidism, and horseshoe kidney), skeletal deformities (scoliosis, radioulnar synostosis, joint laxity, and hip subluxation), endocrinologic anomalies (hypothyroidism), hematologic anomalies (von Willebrand disease), recurrent infections, facial dysmorphisms (frontal bossing, prominent glabella, bitemporal narrowing, down-slanted palpebral fissures, low-set ears, prominent, round, or bullous nasal tip, prominent nasal bridge, and thin upper lip), and abnormal neuroimaging (obstructive hydrocephalus, Chiari malformation, macrocerebellum, and hippocampal atrophy) [218].

SMARCA2-related disorders

Pathogenic variants in the SMARCA2 gene can cause two different syndromes: blepharophimosis-impaired intellectual development syndrome and Nicolaides-Baraitser syndrome.

Blepharophimosis-impaired intellectual development syndrome (MIM#619293)

This neurodevelopmental disorder is due to monoallelic pathogenic variants in the SMARCA2 gene (MIM*600014). It is an autosomal dominant disorder; however, all the variants occurred de novo. The syndrome is associated with variable phenotypes and severity. Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances (low frustration tolerance, clumsiness, overfriendliness, and hand stereotypies), autistic features, growth failure (short stature and underweight), delayed bone age, seizures, hypotonia, spasticity, ocular anomalies (ptosis, cortical visual impairment, astigmatism, hyperopia, myopia, and esotropia), microcephaly, cardiovascular malformations (pulmonary hypertension, patent ductus arterisus, and supraventricular tachycardia), skeletal deformities (joint laxity, scoliosis, small distal phalanges, and nail hypoplasia), genitourinary anomalies (hypoplastic labia and cryptorchidism), gastrointestinal anomalies (gastroesophageal reflux and feeding problems), respiratory anomalies (recurrent pneumonia and bronchitis), facial dysmorphisms (hypertrichosis, sparse hair scalp, low anterior hairline, synophrys, thick eyebrows, long eyelashes, blepharophimosis, narrow palpebral fissures, epicanthal folds, posteriorly rotated ears, anteverted earlobes, broad nasal bridge, upturned nasal tip, large mouth, thin upper lip, and short or long philtrum), and abnormal neuroimaging (cerebral atrophy, thin corpus callosum, pons hypoplasia, ventriculomegaly, and fused sagittal sutures) [219].

Nicolaides-Baraitser syndrome (MIM#601358)

This syndrome is due to monoallelic pathogenic variants in the SMARCA2 gene (MIM*600014). It is an autosomal dominant disorder; however, most variants occur de novo [220].

Affected individuals present with developmental delay, cognitive impairment, behavioral disturbances (tantrums and aggression), autistic features, growth failure, seizures, hypotonia, microcephaly, skeletal deformities (scoliosis, brachydactyly, short phalanges, short metatarsals and carpals, prominent interphalangeal joints and distal phalanges, and cone-shaped epiphyses), genitourinary anomalies (cryptorchidism), gastrointestinal anomalies (feeding difficulties), obesity, eczema, and facial dysmorphisms (aged appearance, low anterior hairline, sparse hair, hypotrichosis or complete alopecia, triangular face, thick overfolded helices of ears, loss of eyebrows, dense eyelashes, narrow and down-slanted palpebral fissures, sagging periorbital skin, narrow nasal bridge, broad nasal base, upturned nasal tip, anteverted nares, thick alae nasi, broad and long philtrum, everted lower lip, thin upper and thick lower lips, widely spaced teeth, thick protruding tongue, large mouth, wrinkly and pale skin, and sandal gap) [220,221,222].

ACTL6B-related disorders

Pathogenic variants in the ACTL6B gene can cause two different syndromes: intellectual developmental disorder with severe speech and ambulation defects and developmental and epileptic encephalopathy 76.

Intellectual developmental disorder with severe speech and ambulation defects (MIM#618470)

This syndrome is due to monoallelic pathogenic variants in the ACTL6B gene (MIM*612458). It is an autosomal dominant disorder; however, all reported pathogenic variants occurred de novo. Affected individuals have developmental delay, cognitive impairment, behavioral disturbances (stereotypies), autistic features, seizures, hypotonia, microcephaly, wide-based gait, skeletal deformities (short distal phalanges and small nails), facial dysmorphisms (hypertelorism, wide and prominent forehead, bulbous nose, wide mouth, and diastema), and abnormal neuroimaging (periventricular gliosis, thin corpus callosum, and brain atrophy) [223].

Developmental and epileptic encephalopathy 76 (MIM#618468)

This syndrome is due to biallelic pathogenic variants in the ACTL6B gene (MIM*612458) and is inherited in an autosomal recessive pattern. It is characterized by early onset drug-resistant seizures, severe developmental delay, and early death in childhood with an average death age of 3.5 years [223,224,225].

Affected individuals have developmental delay, cognitive impairment, autistic features, growth failure, seizures, hypertonia, axial hypotonia, dystonia, microcephaly, ocular anomalies (cortical visual impairment, strabismus, and poor eye contact), skeletal deformities (kyphoscoliosis and thorax abnormalities), dental anomalies (misalignment), muscular atrophy, gastrointestinal anomalies (poor feeding, dysphasia, and anal stenosis), respiratory abnormalities (recurrent cases of pneumonia), facial dysmorphisms (large ears, frontal bossing, deep-set eyes, open mouth, high-arched palate, and downturned mouth corners), and abnormal neuroimaging (hypomyelination, corpus callosum hypoplasia or agenesis, brain atrophy, ventricular dilation, posterior colpocephaly, hypoplasia of cerebellar vermis, focal cortical dysplasia, and asymmetric gyral pattern) [223,224,225].

ATRX-related disorders

Pathogenic variants in the ATRX gene can cause two different syndromes: alpha-thalassemia/impaired intellectual development syndrome and X-linked intellectual disability-hypotonic facies syndrome. Both disorders are associated with variable phenotypes.

Alpha-thalassemia/impaired intellectual development syndrome (MIM#301040)

This syndrome is due to pathogenic variants in the ATRX gene (MIM*300032) and is inherited in an X-linked dominant pattern. Affected individuals present with developmental delay, cognitive impairment, behavioral disturbances (self-injury and prolonged periods of laughing or screaming), growth failure, neonatal hypotonia, spasticity, seizures, hearing impairment, ocular anomalies (entropion, blepharitis, conjunctivitis, iris coloboma, entropion, optic atrophy, and vision impairment), microcephaly, short stature, hematological anomalies (alpha thalassemia, mild form of hemoglobin H disease, or mild hypochromic microcytic anemia), cardiovascular malformations (tetralogy of Fallot, septal defects, pulmonary and aortic stenosis, transposition of great arteries, patent ductus arteriosus, and dextrocardia), skeletal deformities (fixed flexion deformities of joints, delayed bone age, coxa valga, drumstick distal phalanges, tapering fingers, brachydactyly, clinodactyly, bifid thumb, overriding toes, varus or valgus deformities of feet, chest wall deformity, hemivertebrae, spina bifida, scoliosis, and kyphosis), genitourinary anomalies (small kidneys, renal agenesis, hydronephrosis, ureteropelvic junction obstruction, bladder extrophy, urethral stricture or diverticulum, small penis, hypospadias, cryptorchidism, and shawl scrotum), gastrointestinal anomalies (gut dysmotility, hiatal hernia, hematemesis, recurrent small bowel obstruction, volvulus, Hirschsprung disease, constipation, and diarrhea), respiratory anomalies (apnea and pneumonia), and facial dysmorphisms (midface hypoplasia, small, posteriorly rotated and low-set ears, hypertelorism, epicanthal folds, small triangular nose, low nasal bridge, anteverted nares, protruding tongue, full lips, open mouth, and widely spaced upper incisors) [226,227,228,229].

X-linked intellectual disability-hypotonic facies syndrome (MIM#309580)

This syndrome is due to pathogenic variants in the ATRX gene (MIM*300032) and is inherited in an X-linked recessive pattern. Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances (hyperactivity, paroxysmal bursts of laughter, repetitive behavior, self-stimulatory behavior, fingers in mouth, and self-absorbed), growth failure with short stature, hearing impairment, ocular anomalies (exotropia, ptosis, and optic atrophy), hypotonia, lower limb hypertonia, seizures, microcephaly, hematologic anomalies (mild alpha thalassemia), genitourinary anomalies (bilateral renal hypoplasia, cryptorchidism, hypospadias, and small penis), gastrointestinal anomalies (feeding difficulties, gastroesophageal reflux, gastric dysmotility, vomiting, feeding difficulties, and constipation), skeletal deformities (equinovarus deformity), neoplasia (osteosarcoma), facial dysmorphisms (dolichocephaly, narrow face, epicanthal folds, telecanthus, up-slanted palpebral fissures, short nose, anteverted nostrils, micrognathia, macrostomia, tented upper lip, cleft palate, widely spaced upper central incisors, protrusion of the tongue, and short, tapering, and overlapping toes), and abnormal neuroimaging (cortical atrophy and white matter abnormalities) [230,231,232,233].

SRCAP-related disorders

Pathogenic variants in the SRCAP gene can cause two different syndromes: Floating-Harbor syndrome and developmental delay, hypotonia, musculoskeletal defects, and behavioral disturbances.

Floating-Harbor syndrome (MIM#136140)

This syndrome is due to monoallelic pathogenic variants in the SRCAP gene (MIM*611421) and is inherited in an autosomal dominant manner. Most pathogenic variants occurred de novo. Affected people exhibit developmental delay, cognitive impairment, behavioral disturbances (rigidity, attention deficit hyperactivity disorder, sleep disturbances, and aggression), psychiatric manifestations (anxiety and obsessions), seizures, short stature, hearing impairment, ocular anomalies (strabismus and hyperopia), microcephaly, cardiovascular malformations (atrial septal defects, aortic coarctation, persistent left superior vena cava, and aneurysms of internal carotids), skeletal deformities (hypoplasia of maxilla, brachydactyly, clinodactyly, broad thumbs, fingertips, and first toes, hypermobile and extensible fingers, pseudoarthrosis of the clavicle, missing ribs, hip dysplasia, and cone shaped epiphyses), dental anomalies (small teeth, supernumerary incisors, and malocclusions), gastrointestinal anomalies (constipation and celiac disease), genitourinary anomalies (hydronephrosis, nephrocalcinosis, posterior urethral valve, hypospadias, inguinal hernia,varicoceles, epididymal cysts, and cryptorchidism), endocrine anomalies (primary ovarian insufficiency, delayed puberty, hypermenorrhea, delayed bone age, and hypothyroidism), neoplasia (intramedullary ganglioglioma), facial dysmorphisms (triangular face, long eyelashes, deep-seated eyes, low-set and large ears, narrow nasal root, low hanging columella, prominent nose, broad nasal tip, large nares, short philtrum, prognathism, downturned mouth corners, thin upper and everted lower lips, short neck, hirsutism mainly on upper arms and shoulders, low posterior hairline, and high pitched hypernasal voice), and abnormal neuroimaging (tethered cord) [234,235,236,237,238,239].

Developmental delay, hypotonia, musculoskeletal defects, and behavioral disturbances (MIM# 619595)

This syndrome is due to monoallelic pathogenic variants in the SRCAP gene (MIM*611421). It is inherited in an autosomal dominant manner with variable and nonspecific phenotypes. Most pathogenic variants occur de novo [62]. Affected individuals have developmental delay, cognitive impairment, behavioral disturbances (tics, Tourette syndrome, attention deficit hyperactivity disorder, and anger), autistic features, psychiatric manifestations (anxiety, schizophrenia, and psychosis), hypotonia, seizures, ocular anomalies (myopia or hypertropia), skeletal deformities (scoliosis, pectus excavatum or carinatum, and joint hypermobility), gastrointestinal anomalies (gastroesophageal reflux), respiratory anomalies (laryngotracheomalacia), and facial dysmorphisms (long face, prominent forehead, prominent ears, periorbital fullness, epicanthal folds, narrow palpebral fissures, wide nasal bridge, wide mouth, and retrognathia or prognathism) [62].

Disorders of epigenetic readers

Four syndromes have been associated with defects in one of the genes coding for epigenetic readers (Table 2).

Intellectual developmental disorder with dysmorphic facies and ptosis (MIM#617333)

This syndrome is due to monoallelic pathogenic variants in the BRPF1 gene (MIM*602410). It is inherited in an autosomal dominant manner and most variants occur de novo [240].

Affected individuals have developmental delay, cognitive impairment, behavioral abnormalities (shyness, attention deficit hyperactivity disorder, and limited social interaction), autistic spectrum disorder, psychiatric manifestations (anxiety and obsessive–compulsive disorder), growth failure, seizures (absence epilepsy), microcephaly, hypotonia, hyperreflexia, clonus, ocular anomalies (ptosis, blepharophimosis, strabismus, myopia, hypermetropia, nystagmus, amblyopia, photophobia, deuteranomaly, and unequal pupil dilation), cardiovascular malformations (cardiomyopathy, patent ductus arteriosus, patent foramen ovale, and dilation of proximal aorta), respiratory anomalies (sleep apnea, laryngomalacia, tracheomalacia, and vocal cord paralysis), musculoskeletal deformities (joint hypermobility, torticollis, Madelung deformity, hip dysplasia, club feet, camptodactyly, and long first toe), inguinal hernia, gastrointestinal anomalies (feeding difficulties, gastroparesis, and gastroesophageal reflux), immunologic anomalies (eczema, food allergy, serum sickness, Henoch-Schoenlein purpura, urticarial vasculitis, and juvenile onset arthritis), urogenital anomalies (hydronephrosis, pyelonephritis, and cryptorchidism), endocrinologic anomalies (hypothyroidism, hyperketotic hypoglycemia, and polycystic ovary syndrome), facial dysmorphisms (round face, temporal narrowing, flat facial profile, thick and coarse hair, epicanthus inversus, protruding, small, and round ears, hypertelorism, down-slanted palpebral fissures, almond eyes, bulbous or pear-shaped nose, broad nasal bridge, anteverted nostrils, long philtrum, downturned mouth, thin lips, retrognathia, high palate, and asymmetric crying face), and abnormal neuroimaging (brain atrophy, anterior cingulate cortex rostrum, corpus callosum hypoplasia, decreased white matter decreased, prominent cistern magna, and cervical spine fusion) [240,241,242,243].

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (MIM#617755)

This neurodevelopmental disorder is caused by monoallelic pathogenic variants in the BPTF gene (MIM*601819). It is an autosomal dominant disorder with variable phenotypes. Most variants occurred de novo [72, 244].

Affected individuals present with developmental delay, cognitive impairment, growth failure, psychiatric manifestations (depression and anxiety), seizures (generalized tonic–clonic, staring spells, and complex focal seizures), hypotonia, microcephaly, ocular anomalies (cataracts, strabismus, myopia, and hyperopia), cardiovascular malformations (transposition of the great arteries, ventricular sepal defect and left ventricular failure), skeletal deformities (metopic synostosis, spinal abnormalities, scoliosis, kyphosis, limb-length discrepancies, small hands, fetal fingertip pads, clinodactyly, slender fingers, flat feet, sandal gap, broad halluces, and overlapping toes), gastrointestinal anomalies (feeding difficulties, gastroesophageal reflux, and constipation), endocrinologic abnormalities (hypothyroidism, diabetes, and hypercholesterolemia), immunologic abnormalities (recurrent oral ulcers and bacterial infections), dermatologic manifestations (café au lait macules, cutis marmorata, and hyperhidrosis), hematologic abnormalities (bleeding tendency), genitourinary abnormalities (polycystic kidneys, horseshoe kidney, and cryptorchidism), facial dysmorphisms (brachycephaly, synophrys, eyebrows flared laterally, hypertelorism, up-slanted and short palpebral fissures, epicanthal folds, flat cheek bones, prominent and tubular nose, broad nasal tip, long nasal bridge, hypoplastic alae nasi, micrognathia, thin upper lip, and longue tongue), and abnormal neuroimaging (pituitary hypoplasia, and white matter abnormalities) [72, 244].

Cornelia de Lange syndrome-6 (MIM## 620568)

This syndrome is caused by monoallelic pathogenic variants in the BRD4 gene (MIM*608749). It is an autosomal dominant disorder with variable severity. Most variants occur de novo [245].

Affected individuals usually present with developmental delay, cognitive impairment, behavioral abnormalities (hyperphagia, trichotillomania, hypersexuality, and aggression), psychiatric manifestations (disruptive mood dysregulation disorder, intermittent explosive disorder, schizophrenia, obsessive–compulsive disorder, and dissociative identity disorder), growth failure, microcephaly, cardiovascular malformations (ventricular septal defect), skeletal deformities (radial anomalies and bilateral syndactyly), skin abnormalities (hypertrichosis), gastrointestinal abnormalities (hiatal hernias), genital anomalies (hypospadias), and facial dysmorphisms (frontal upsweep of hair, large ears, synophrys, arched and sparse eyebrows, hypertelorism, down-slanted palpebral fissures, short nose, anteverted nostrils, long philtrum, cleft lip, and prominent incisors) [245, 246].

X-linked intellectual developmental disorder-93 (MIM#300659)

This disorder is caused by pathogenic variants in the BRWD3 gene (MIM*300553). It is an X-linked disorder that mainly affects males. Females may have milder manifestations. Affected individuals present with developmental delay, cognitive impairment, behavioral abnormalities (shyness and attention deficit hyperactivity disorder), autistic spectrum disorder, overgrowth, hypotonia, macrocephaly, genitourinary abnormalities (cryptorchidism), skeletal deformities (kyphosis, pectus excavatum, sharp distal phalanges of the hands, and flat feet), and facial dysmorphisms (prominent and large ears, cupped ear helices, triangular face, frontal bossing, deep-seated eyes, and pointed chin) [247, 248].

Overlap in the phenotypes of histone-related syndromes

Currently, there are 72 histone-related disorders which include 7 syndromes caused by defects in histone genes, 35 syndromes due to histone modifications defects, 26 syndromes due to defects in chromatin remodeling, and 4 due to defects in epigenetic readers. These syndromes have multisystem manifestations considering that these defects can change the expression of many genes with diverse roles. As the nervous system needs specific patterns of gene expression, these aberrations are expected to have a profound influence on neurodevelopment [92].

Almost all histone-related syndromes are associated with cognitive impairment and developmental delay (71/72, 99%) and the vast majority have distinctive facial features (69/72, 96%). In addition, other variable neurological manifestations include hypotonia (58/72, 81%), behavioral disturbances (56/72, 78%), seizures (54/72, 75%), microcephaly (41/72, 57%), and spasticity (12/72, 17%). Ocular manifestations (57/72, 79%) and hearing impairment (34/72, 47%) are common. Growth failure (43/72, 60%) is also common, but some syndromes are associated with overgrowth (7/72, 10%). Histone-related disorders are characterized by congenital anomalies affecting multiple organs. Among these are skeletal (69/72, 96%), gastrointestinal (49/72, 68%), genitourinary (48/72, 67%), and cardiovascular (39/72, 54%) anomalies (Table 2).

To explore facial phenotype similarity within and between these syndromes, frontal facial photographs of individuals diagnosed with histone-related syndromes were analyzed using the GestaltMatcher algorithm (FDNA Inc., USA). The GestaltMatcher algorithm is a computational tool that converts facial characteristics captured by a photograph into numerical descriptors, allowing for quantitative comparison and clustering of facial phenotypes. The tool is part of Face2Gene (FDNA Inc., USA), a HIPAA-compliant platform that enables the interaction of different algorithms to analyze patients’ facial phenotypes and can be leveraged for syndrome classification (lump and splitting), phenotype delineation, and patient clustering based on facial phenotype. These numerical descriptors can be considered high-dimensional coordinates in the Clinical Face Phenotype Space (CFPS). The smaller the distances between patient coordinates, the more similar their facial phenotypic features are [249, 250].

Through a literature search, published facial photos were obtained for 45 histone-related syndromes. For each syndrome, we analyzed intra-group similarity, by computing the pairwise cosine similarity between all patients’ descriptors within each syndrome. Cosine similarity is a measure of similarity between two vectors, computed by finding the cosine of the angle between them. By considering the absolute value of cosine similarity, we measure the strength of the relationship between two vectors, ignoring direction. It ranges from 0 (completely dissimilar) to 1 (identical or completely opposite), making it useful in cases where only the magnitude of similarity matters, such as clustering or distance-based applications. Intra-group similarity is a measure of homogeneity within a syndrome, reflecting how alike patients are in terms of facial phenotype. Higher intra-group similarity suggests that patients diagnosed with a syndrome are closely aligned in terms of facial phenotype, whereas lower values indicate greater diversity in facial phenotype for that syndrome (Fig. 4).

Fig. 4

Intra-syndrome facial phenotype similarity. A bar plot presenting intra-group cosine similarity between facial phenotype descriptors for histone-related syndromes, including sample size information (n). Darker green values correspond to larger sample sizes. Top 10 syndromes with the highest intra-group similarity: IDDAM, Stolerman, Bryant, IDDSSAD, Rahman, NEDSID, Snijders, CHARGE, Kleefstra, and Wiedemann. (ArboledA: Arboleda–Tham syndrome; ATRX: Alpha-thalassemia/impaired intellectual development syndrome; BIS: Blepharophimosis- impaired intellectual development syndrome; Bryant: Bryant–Li–Bhoj neurodevelopmental syndrome; Claes: Claes–Jensen syndrome; Coffin: Coffin–Siris syndrome; Cornelia: Cornelia De Lange syndrome; Diets: Diets–Jongmans syndrome; DYT: Childhood-onset dystonia 28; Floating: Floating-Harbor syndrome; HH5: Hypogonadotropic hypogonadism 5 with or without anosmia; IDDAM: Intellectual development disorder with autism and macrocephaly; IDDSELD: Intellectual development disorder with seizures and language delay; IDDSSAD: Intellectual developmental disorder with severe speech and ambulation defects; Luscan: Luscan Lumish syndrome; Menke: Menke–Hennekam syndrome; NEDSID: Neurodevelopmental disorder with speech impairment and dysmorphic facies; Rauch: Rauch–Steindl syndrome; Rubinstein: Rubinstein–Taybi syndrome; Say: Barber Say syndrome; Siderius: Siderius X-linked intellectual developmental disorder; Sifrim: Sifrim–Hitz-Weiss syndrome; Snijders: Snijders Blok–Campeau syndrome; Stolerman: Stolerman neurodevelopmental syndrome; Suleiman: Suleiman–El-Hattab syndrome; Tessadori: Tessadori-Van Haaften neurodevelopmental syndrome; Wiedemann: Wiedemann–Steiner syndrome)

Additionally, we explored inter-group similarity, examining how similar the facial phenotypic features of histone-related syndromes are to each other. To enhance the reliability and generalizability of similarity computations between these syndromes, we leveraged intra-group similarity to select syndrome clusters with greater homogeneity in facial features. From the original 45 syndromes, 11 were excluded where the intra-group similarity was below 0.1 or the sample size was smaller than 5, so that the remaining syndrome clusters more accurately represent the target populations. The inter-group similarity was then estimated for the remaining 34 syndromes. To achieve this, the average of the facial phenotype descriptors of the patients for each syndrome was computed, obtaining the centroid of each syndrome cluster. The cosine similarity between centroids for every pair of syndromes was then calculated. This analysis is presented in the syndrome Pairwise Comparison Matrix (sPCM). This analysis revealed high facial phenotype similarity between histone-related syndromes, which share defects in a common pathway (Fig. 5).

Fig. 5

Inter-syndrome facial phenotype similarity. A syndrome Pairwise Comparison Matrix (sPCM), presenting inter-group cosine similarity between facial phenotype descriptors for histone-related syndromes. Darker green values correspond to a higher similarity in facial phenotypic features between the two syndromes. The sPCM diagonal shows a similarity of 1 when each syndrome is compared to itself. Top 10 syndrome pairs with highest inter-group similarity: Say-Weaver, Rauch-Say, CHARGE-Say, Cornelia-Luscan, Kleefstra-Rahman, Kleefstra-Stolerman, Say-Tessadori, DYT-Say, Kleefstra-Luscan, Luscan-Say. (ArboledA: Arboleda–Tham syndrome; ATRX: Alpha-thalassemia/impaired intellectual development syndrome; BIS: Blepharophimosis- impaired intellectual development syndrome; Bryant: Bryant–Li–Bhoj neurodevelopmental syndrome; Claes: Claes–Jensen syndrome; Coffin: Coffin–Siris syndrome; Cornelia: Cornelia De Lange syndrome; Diets: Diets–Jongmans syndrome; DYT: Childhood-onset dystonia 28; Floating: Floating-Harbor syndrome; HH5: Hypogonadotropic hypogonadism 5 with or without anosmia; IDDAM: Intellectual development disorder with autism and macrocephaly; IDDSELD: Intellectual development disorder with seizures and language delay; IDDSSAD: Intellectual developmental disorder with severe speech and ambulation defects; Luscan: Luscan Lumish syndrome; Menke: Menke–Hennekam syndrome; NEDSID: Neurodevelopmental disorder with speech impairment and dysmorphic facies; Rauch: Rauch–Steindl syndrome; Rubinstein: Rubinstein–Taybi syndrome; Say: Barber Say syndrome; Siderius: Siderius X-linked intellectual developmental disorder; Sifrim: Sifrim–Hitz-Weiss syndrome; Snijders: Snijders Blok–Campeau syndrome; Stolerman: Stolerman neurodevelopmental syndrome; Suleiman: Suleiman–El-Hattab syndrome; Tessadori: Tessadori-Van Haaften neurodevelopmental syndrome; Wiedemann: Wiedemann–Steiner syndrome)

Conclusions and future directions

Histones are necessary for epigenetic gene expression regulation. To date, 72 histone-related disorders have been described as defects in histone genes, histone modifications, chromatin remodeling, or epigenetic readers. These disorders are linked to multisystem manifestations and are expected to have a profound influence on neurodevelopment. Many genes coding histone proteins, histone modification enzymes, chromatin remodeling subunits, and epigenetic readers have not yet been associated with human disease. However, with the accelerated utility of genome and exome sequencing in assessing people with neurodevelopmental disorders, future discoveries are likely to unveil more novel disorders associated with histones. While the approach to managing these syndromes remains symptomatic, a wider comprehension of cellular and molecular mechanisms could pave the way for future clinical studies aiming to explore an approach for precision therapies.