Research highlights widespread epigenetic defects in the human genome

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A study shows, for the first time, that epigenetic defects in the human genome are widespread, and occur at hundreds of genes known to cause genetic diseases.

“Because the epigenetic variants we identify would not be detected by genome sequencing, yet can lead to the dysregulation and silencing of genes known to be linked with heritable diseases, our work shows that some types of disease-causing mutations will be missed by standard genetic testing that only looks at DNA sequence,” said Andrew Sharp, Ph.D., associate professor, genetics and genomic sciences, Icahn School of Medicine at Mount Sinai.

The research team led by Dr. Sharp studied DNA methylation profiles of more than 23,000 people, resulting in the first large-scale population survey of rare epigenetic defects in the human genome.

The team identified thousands of epivariations, for the first time showing that these are relatively prevalent events in humans.

They also demonstrated that they are frequently associated with abnormal gene expression, and many of these are predicted to effect genes that are known to underlie Mendelian diseases.

The reported findings indicate that epivariations likely contribute to a significant fraction of many different types of genetic disease.

The study also provides many novel insights into the underlying causes and biology of epivariations, and show that while some are caused by rare sequence variation that disrupts regulatory elements, about one third occur somatically.

Thus, while some epivariations are likely heritable events, others would likely not be passed on to subsequent generations. Further analysis of the data also identified many novel CGG repeat expansions underlying some epivariations.

Isolated reports of epigenetic defects causing genetic diseases, including hereditary breast and colon cancers, have appeared in the literature over the past decade.

However, these were thought to be very rare events. The researchers sought to identify the prevalence of this type of mutation in the human genome, determine their potential impact on all types of Mendelian diseases, and to gain insight into the underlying causes and biology of epivariations.


The epigenetic machinery in conjunction with the transcriptional machinery is responsible for maintaining genome-wide chromatin states and dynamically regulating gene expression. Mendelian disorders of the epigenetic machinery (MDEMs) are genetic disorders resulting from mutations in components of the epigenetic apparatus.

Though individually rare, MDEMs have emerged as a collectively common etiology for intellectual disability (ID) and growth disruption. Studies in model organisms and humans have demonstrated dosage sensitivity of this gene group with haploinsufficiency as a predominant disease mechanism.

The epigenetic machinery consists of three enzymatic components (writers, erasers and chromatin remodelers) as well as one non-enzymatic group (readers).

A tally of the entire census of such factors revealed that although multiple enzymatic activities never coexist within a single component, individual enzymatic activities often coexist with a reader domain.

This group of disorders disrupts both the chromatin and transcription states of target genes downstream of the given component but also DNA methylation on a global scale.

Elucidation of these global epigenetic changes may inform our understanding of disease pathogenesis and have diagnostic utility.

Moreover, many therapies targeting epigenetic marks already exist, and some have proven successful in treating cancer.

This, along with the recent observation that neurological dysfunction in these disorders may in fact be treatable in postnatal life, suggests that the scientific community should prioritize this group as a potentially treatable cause of ID.

Here we summarize the recent expansion and major characteristics of MDEMs, as well as the unique therapeutic prospects for this group of disorders.

With the advent of clinical exome sequencing, Mendelian disorders of the epigenetic machinery (MDEMs)—also known as chromatin modifying disorders—have emerged as one of the most rapidly expanding groups (1,2). In 2014, we compiled a list of 34 conditions due to mutations in 28 genes (1).

By 2015, there were 44 such disorders (2), and the list continues to expand. Here, we have taken a more systematic approach that builds on recent work (www.epigeneticmachinery.org) (3) and have included only those components of the epigenetic machinery with an identifiable domain conferring one or more of the above functions—writer, eraser, reader or remodeler—and have identified 82 human conditions resulting from mutations in 70 epigenetic machinery genes.

Notably, this approach excludes some related conditions, and for this reason and ongoing discovery, will always be an underestimate. Despite this, our observations reveal common phenotypes and highlight the fact that many of the enzymatic factors also contain a reader domain, conferring dual function. In addition, we briefly review new developments related to molecular pathogenesis and outline potential novel therapeutic strategies.

The MDEMs

Table 1 – Summary of disease-causing components of the epigenetic machinery

GeneConditionFunctionInheritanceCognitionGrowthHeightHeadCraniofacial dysmorphismOther phenotypesChr
SMARCA4 Coffin–Siris syndrome 4
Rhabdoid tumor
predisposition syndrome 
Remodeler/Reader AD
AD 
ID
Normal 
Abnormal
Normal 
Short stature
Normal 
Microcephaly
Normal 
Y
Neurobehavioral, hypotonia, limb, hair.
None 
Auto 
SMARCA2 Nicolaides–Baraitser syndrome Remodeler/Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, hair, limb Auto 
ATRX ATRX syndrome Remodeler/Reader X-linked dominant (XLD) ID Abnormal Short stature Microcephaly Neurobehavioral, musculoskeletal (MSK), thalassemia, hypotonia, genitourinary (GU) 
CHD2 Epileptic encephalopathy, childhood onset Remodeler/Reader AD ID Abnormal Normal Microcephaly Neurobehavioral Auto 
CHD8 Autism susceptibility 8/overgrowth and ID Remodeler/Reader AD ID Abnormal Tall stature Macrocephaly Neurobehavioral Auto 
CHD4 Sifrim–Hitz–Weiss syndrome Remodeler/Reader AD ID Abnormal Normal Macrocephaly Neurobehavioral, hearing loss (HL), GU, MSK, congenital heart disease (CHD) Auto 
CHD1 Pilarowski–Bjornsson syndrome Remodeler/Reader AD ID Abnormal Short stature Macrocephaly Neurobehavioral, hypotonia Auto 
CHD3 Snijders Blok–Campeau syndrome Remodeler/Reader AD ID Abnormal Normal Macrocephaly Neurobehavioral Auto 
CHD7 CHARGE Remodeler/Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, eye, CHD, GU, HL, limb Auto 
 Hypogonadotropic hypogonadism  AD Normal Normal Normal Normal HL, endocrine (endo)/GU, hypo-/anosmia, cleft lip/palate  
SRCAP Floating–Harbor syndrome Remodeler AD ID Abnormal Short stature Normal Neurobehavioral, MSK Auto 
SETD5 Mental retardation autosomal dominant (MRAD) 23 Writer AD ID Normal Normal Normal Neurobehavioral, abdominal wall/gastrointestinal (GI) anomalies, MSK Auto 
PRDM12 Hereditary sensory and autonomic neuropathy 8 Writer AR Normal Normal Normal Normal Insensitivity to pain/temperature Auto 
PRDM16 Dilated cardiomyopathy Writer AD Normal Normal Normal Normal Other cardiac findings Auto 
PRDM5 Brittle cornea syndrome Writer AR Normal Normal Normal Normal Eye, MSK, skin Auto 
KMT5B MRAD 51 Writer AD ID Abnormal Tall stature Macrocephaly Neurobehavioral, eye, MSK Auto 
SETD2 Luscan–Lumish syndrome Writer AD ID Abnormal Tall stature (short stature) Macrocephaly Neurobehavioral, MSK Auto 
EZH2 Weaver syndrome Writer AD ID Abnormal Tall stature Macrocephaly Neurobehavioral, hypotonia, MSK, limb Auto 
DNMT3A Tatton-Brown-Rahman syndrome Writer/Reader AD ID Abnormal Tall Stature Macrocephaly Neurobehavioral, hypotonia, MSK Auto 
 Microcephalic dwarfism    Abnormal Short stature Microcephaly NA MSK 
NSD1 Sotos syndrome Writer/Reader AD ID Abnormal Tall stature Macrocephaly Neurobehavioral, hypotonia, MSK, CHD, GU Auto 
DNMT1 AD cerebellar ataxia deafness and narcolepsy/Hereditary sensory neuropathy 1E Writer/Reader AD Normal initially,
neurodegeneration 
Normal Normal Normal Neurobehavioral, HL Auto 
KMT2B Childhood-onset dystonia 28 Writer/Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, eye Auto 
EHMT1 Kleefstra syndrome Writer/Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, hypotonia, CHD, GU, HL, immune dysfunction (dys) Auto 
KMT2C Kleefstra syndrome 2 Writer/Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, hypotonia, MSK Auto 
CREB-binding protein (CREBBP) Rubinstein–Taybi syndrome 1 Writer/Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, GU, limb, immune dys/recurrent infections, MSK, eye, CHD, GI Auto 
EP300 Rubinstein-Taybi syndrome 2 Writer/Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, GU, limb, MSK, eye, GI, skin, CHD, immune dys/recurrent infections Auto 
KAT6A MRAD 32 Writer/Reader AD ID Abnormal Normal Microcephaly Neurobehavioral, abnormal (abnl) muscle tone, CHD, GI Auto 
KAT6B Say–Barber–Biessecker–Young–Simpson syndrome Writer/Reader AD ID Abnormal Normal Microcephaly Neurobehavioral, hypotonia, MSK, GU, CHD, HL, eye Auto 
 Genitopatellar syndrome  AD ID Abnormal Normal Microcephaly Neurobehavioral, hypotonia, MSK, GU, CHD  
WHSC1 Wolf–Hirschhorn syndrome Writer/Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, MSK, CHD, HL Auto 
KMT2E KMT2E deficiency Writer/Reader AD ID Abnormal Unknown Macro/microcephaly Neurobehavioral, hypotonia Auto 
ASH1L MRAD 52 Writer/Reader AD ID Normal Normal Normal Neurobehavioral, eye, MSK, GU Auto 
DNMT3B Immunodeficiency-centromeric instability-facial anomalies syndrome Writer/Reader AR ID Abnormal Short stature Microcephaly Neurobehavioral, immune dys/recurrent infections Auto 
KMT2A Wiedemann–Steiner syndrome Writer/Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, skeletal, immune dys, hair, eye Auto 
KMT2D Kabuki syndrome 1 Writer/reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, hypotonia, MSK, immune dys, CHD, limb Auto 
KDM6A Kabuki syndrome 2 Eraser XLD ID Abnormal Short stature Microcephaly Neurobehavioral, hypotonia, MSK, immune dys, CHD, limb 
histone deacetylase (HDAC)4 Brachydactyly mental retardation Eraser AD ID Abnormal Short stature Normal Neurobehavioral, limb, MSK Auto 
HDAC6 Chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly and microphthalmia Eraser XLD ID Abnormal Short stature Macrocephaly Neurobehavioral, MSK, eye 
HDAC8 Cornelia De Lange syndrome, type 5 Eraser XLD ID Abnormal Short stature Microcephaly Neurobehavioral, MSK, limb, hair, HL, GI, GU, CHD 
HR Alopecia universalis
Atrichia with papular lesions
Hypotrichosis type 4 
Eraser AR
AR
AD 
Normal
Normal
Normal 
Normal
Normal
Normal 
Normal
Normal
Normal 
Normal
Normal
Normal 
N
N
All 3 limited to reduced hair growth Auto 
KDM1A Cleft palate, psychomotor retardation, and distinctive facial features Eraser AD ID Abnormal Short stature Macrocephaly Neurobehavioral, hypotonia, MSK, eye Auto 
KDM6B KDM6B deficiency Eraser AD ID Abnormal Short stature Macrocephaly Neurobehavioral, hypotonia Auto 
KDM5C Claes–Jensen X-linked mental retardation (XLMR) Eraser/Reader X-linked recessive (XLR) ID Abnormal Short stature Micro/Macrocephaly Neurobehavioral, MSK, hair, GU 
KDM5B Mental retardation autosomal recessive 65 Eraser/Reader AD/AR ID Normal Normal Normal Neurobehavioral, eye, limb Auto 
PHF8 Siderius XLMR Eraser/Reader XLR ID Normal Normal Normal MSK (cleft lip/palate) 
TAF1 XLMR 33 Reader XLR ID Abnormal Short stature Microcephaly Neurobehavioral, hypotonia, ear, eye, MSK 
RAI1 Smith–Magenis syndrome Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, hypotonia, ear, eye, MSK, CHD, GU Auto 
AIRE Autoimmune polyendocrinopathy syndrome 1 Reader AD/AR Normal Normal Normal Normal Immune dys, endo, ectodermal, GI, vascular Auto 
ALG13 Eary infantile epileptic encephalopathy 36 Reader XLD ID Normal Normal Normal Neurobehavioral 
ASXL1 Bohring–Opitz syndrome Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, MSK, skin/vascular/hair Auto 
ASXL2 Shashi–Pena syndrome Reader AD ID Abnormal Tall stature Macrocephaly Neurobehavioral, hypotonia, MSK, skin/vascular, endo (hypoglycemia), CHD Auto 
ASXL3 Bainbridge–Ropers syndrome Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, MSK Auto 
BPTF Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, limb Auto 
BRPF1 Intellectual developmental disorder with dysmorphic facies and ptosis Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, hypotonia, eye Auto 
BRWD3 XLMR 93 Reader XLR ID Abnormal Tall stature Macrocephaly Neurobehavioral, GU 
CBX2 Sex reversal Reader AR Normal Normal Normal Normal Unknown Sex reversal Auto 
EED Cohen–Gibson syndrome Reader AD ID Abnormal Tall stature Macrocephaly Neurobehavioral, hypotonia, MSK, skin Auto 
LBR Pelger–Huet anomaly (PHA) Reader AD Normal Normal Normal Normal Hematologic only Auto 
 PHA with muskuloskeletal findings  AR ID Abnormal Short stature Macro/microcephaly Neurobehavioral, MSK, limb  
 Greenberg skeletal dysplasia  AR Unknown Abnormal Short stature Macrocephaly Perinatal lethal, hydrops, MSK, severe limb  
MBD5 MRAD 1 Reader AD ID Abnormal Short stature Microcephaly Neurobehavioral, hypotonia, MSK Auto 
MECP2 Rett syndrome and related disorders Reader XLD (XLR) ID Abnormal Short stature Microcephaly Neurobehavioral, abnl muscle tone, MSK 
MORC2 Charcot–Marie–Tooth disease 2Z Reader AD ID in some Normal Normal Normal Neuromuscular/neurobehavioral Auto 
MSH6 Hereditary nonpolyposis colorectal cancer 5 Reader AD Normal Normal Normal Normal Cancer predisposition Auto 
 Mismatch repair cancer syndrome  AR Normal Normal Normal Normal Cancer predisposition, skin, brain  
ORC1 Meier–Gorlin syndrome 1 Reader AR ID Abnormal Short stature Microcephaly MSK, HL, GU, respiratory Auto 
PHF6 Borjeson–Forssman–Lehmann syndrome Reader XLR ID Abnormal Short stature Microcephaly Neurobehavioral, GU, MSK, limb 
PHIP Developmental delay, ID, obesity, and dysmorphic features Reader AD ID Unknown Unknown Unknown Neurobehavioral, hypotonia, eye, limb, skin Auto 
RAG2 Omenn syndrome and severe combined immunodeficiency Reader AR Normal Normal Normal Normal Immune dys/recurrent infections Auto 
RERE Neurodevelopmental disorder with or without other anomalies Reader AD ID Abnormal Short stature Unknown Neurobehavioral, hypotonia, eye, heart, GU Auto 
SMN1 Spinal muscular atrophy Reader AR Normal Normal Normal Normal Neuromuscular Auto 
SP110 Hepatic venoocclusive disease and immune deficiency Reader AR Normal Unknown Unknown Unknown Immune dys, vascular Auto 
TDRD7 Cataract 36 Reader AR Normal Normal Normal Normal Eye Auto 
ZMYND11 MRAD 30 Reader AD ID Unknown Unknown Unknown Neurobehavioral Auto 
DPF2 Coffin Siris 7 Reader AD ID 

Previously there has been controversy regarding whether epigenetic modifications play a causal role in determining phenotypes (4).

However, for this class of disorders causality is clear; a genetic defect causes loss of function of an epigenetic component resulting in epigenetic abnormalities (5–7), which lead to phenotypic changes. Most MDEMs are caused by heterozygous loss of function variants in the machinery that maintains epigenetic marks (Fig. 1; Table 1).

The vast majority (83%) are associated with intellectual disability (ID, Fig. 1; Table 1) and many with abnormal growth (Fig. 1; Table 1), indicating that maintenance of normal epigenetic states is important for the fundamental processes of neurological development and growth (1,2).

Many genes are associated with more than one disorder, and when all 82 disorders are considered, 60 (73%) exhibit ID.

The MDEMs. Seventy genes with defined epigenetic domains (reader, writer, eraser, remodeler, middle icons) have been linked to Mendelian phenotypes. The majority of genes cause disease in the heterozygous state (filled circle). Enzyme domains (writer, eraser, remodeler) are mutually exclusive in any given factor but many coexist with a reader domain (gray shading). ID is seen in the vast majority (blue), as are growth abnormalities (orange). A indicates genes on autosomes; X indicates genes on the X chromosome.
The MDEMs. Seventy genes with defined epigenetic domains (reader, writer, eraser, remodeler, middle icons) have been linked to Mendelian phenotypes. The majority of genes cause disease in the heterozygous state (filled circle). Enzyme domains (writer, eraser, remodeler) are mutually exclusive in any given factor but many coexist with a reader domain (gray shading). ID is seen in the vast majority (blue), as are growth abnormalities (orange). A indicates genes on autosomes; X indicates genes on the X chromosome.

The association between MDEMs and neurocognitive deficits in humans is well documented in the literature and has been the focus of much research (1,2,6).

Less is known about the mechanistic links between MDEMs and abnormal growth, a second defining phenotype within this group (1,2).

Tatton-Brown et al. showed that 45% of individuals with overgrowth and ID have mutations in epigenetic machinery genes (8), and studies of MDEMs associated with growth retardation in humans and mice support causality (1,2,9,10).

Using our list of bioinformatically defined disease-causing epigenetic machinery genes (3), disruption of 50 (71%) lead to abnormal growth with 41 (58%) being associated with growth retardation (short stature and/or microcephaly) and 19 (27%) being associated with overgrowth (tall stature and/or macrocephaly; Table 1; Fig. 1).

We (1,2,5) and others (8,10) have observed high co-occurrence of the above phenotypes—ID and abnormal growth—in MDEMs.

In fact, of the 60 MDEMs with ID, 52 (87%) also exhibit some form of abnormal growth (Table 1,Fig. 1).

It may not be surprising that conditions that manifest microcephaly or macrocephaly also exhibit ID (Table 1). However, the connection between ID and tall or short stature is less clear, though mechanisms of altered balance between cellular proliferation and differentiation have been proposed (9,10,11).

In addition to the two most common phenotypes observed in MDEMs, we also note a striking number of additional tissue-diverse phenotypic manifestations in many disorders (2) (Table 1).

These observations fit with the findings of Boukas et al. (3) in which epigenetic machinery genes tend to be highly expressed in all tissues but many are also co-expressed across individuals within those tissues. Co-expression of epigenetic machinery genes could help explain the high dosage sensitivity of these genes (3).

If this co-expression reflects a delicate balance in the entire system of epigenetic components, even a small perturbation in the amount of protein product of one could disrupt this balance (3).

In support of this, epigenetic machinery genes, particularly the coexpressed ones, exhibit high intolerance to loss-of-function variation as indicated by high probability of loss-of-function intolerance (pLI) scores (3), and the vast majority of conditions (55/82 or 67%) are inherited in an autosomal dominant (AD) manner (Table 1; Fig. 1) with de novo mutations leading to haploinsufficiency as the predominant mechanism.

Coexpression appears to be particularly important in neurons as evidenced by neurological phenotypes predominating and the observation that AD inheritance is highly correlated with ID. In fact, these co-occur upon disruption of 63% of our bioinformatically determined list of 70 disease-causing epigenetic machinery genes.

The observation that 43/55 (80%) of the genes linked to ID were previously found to be co-expressed (3) supports this as well.

In contrast, most genes causing autosomal recessive (AR) conditions (71%) are not associated with ID and are instead associated with other tissue-specific features (Table 1, Fig. 1).

In other words, of the 60 conditions with ID, 46 (77%) exhibit AD inheritance and only 4 (7%) exhibit AR inheritance with the remainder being X-linked.

Thus, among the autosome-linked MDEMs, there appear to be two classes – dominant ID syndromes due to disruption of highly dosage-sensitive genes and recessive tissue-specific syndromes due to disruption of less dosage-sensitive genes.

We previously reported that multiple enzymatic activities (writer, eraser, remodeler) never coexist within a single epigenetic machinery component (3).

However, a large proportion of genes with enzyme components do contain a reader domain.

All but 15 genes – 79% of all disease-causing epigenetic machinery genes – have a reader domain, and half of these have predicted dual enzymatic and reader functions (Table 1; Fig. 1).

According to Boukas et al. (3), dual function epigenetic machinery genes appear to be extremely dosage sensitive with ~90% having a pLI score >0.9 and are also strongly enriched in the highly coexpressed subset (P = 0.05, OR = 10.2).

Supporting this, very few dual function genes cause AR disease (Table 1; Fig. 1).

Remarkably, all but one disease-causing dual function epigenetic machinery gene, when disrupted, lead to ID (Table 1; Fig. 1), and disruption of this gene (DNMT1) causes neurodegeneration after a period of normal cognitive development (12).

This suggests that even small perturbations in activity of dual function components are not tolerated and disrupt normal neurological development and/or functioning.

Downstream consequences of MDEMs
We previously proposed that a delicate balance of writers and erasers and the marks they place and remove exist at target genes and that any disruption in this balance could lead to disease, implicating target genes as important in pathogenesis (1).

In support of this, several studies have identified potential target genes and have shown that they and their associated altered relevant epigenetic marks play a key role in pathogenesis (13–17). For instance, in Sotos syndrome due to mutations in NSD1 (18,), two promising downstream target genes have emerged, MEIS1 and APC2 (14,15).

Similarly in KS, which is due to deficiency of either the KMT2D histone methyltransferases (HMT) writer (19) or the KDM6A demethylase eraser (20), RAP1B, has been shown to be a promising downstream target gene (16). In neuronal (11) and chondrocyte (9) cellular models of KS1, altered H3K4me3 and gene expression in hypoxia-responsive genes in the former and Shox2 and other chondrocyte-associated genes in the latter reveal these as potential target genes relevant to ID and growth retardation, respectively (9,11).

In addition to histone modifiers, mutations in chromatin remodelers have been shown to bind to specific target genes and alter chromatin marks. In a neuronal-specific conditional murine model of CHARGE (Coloboma, Heart defects, Choanal Atresia, Retardation of growth and development, Genitourinary abnormalities, and Ear anomalies) syndrome, multiple CHD7 target genes were identified (17).

Finally, a recently described disorder of the DNA methylation machinery illustrates many downstream consequences of MDEMs (10).

Heyn et al. (10) showed that specific mutations in DNMT3A within the proline–tryptophan–tryptophan–proline reader domain abrogate binding to H3K36me3, leading to mistargeting and aberrant DNA hypermethylation of regions normally containing distinct H3K27me3 and in some cases H3K4me3.

This leads to altered expression of developmentally regulated Hox genes, among others, and may ultimately cause precocious differentiation at the expense of cell proliferation, resulting in smaller size of the brain and entire organism (10).

We now know that many human MDEMs are characterized by specific DNA methylation signatures present in blood (21–28). These include disorders of DNA methyltransferase writers like DNMT1-associated AD cerebellar ataxia, deafness and narcolepsy (22), as well as disorders of chromatin remodelers like Floating–Harbor syndrome (23) and disorders of dual function components like ATRX (Alpha-Thalassemia/Mental Retardation Syndrome, X-linked) syndrome (24).

A highly sensitive and specific genome-wide DNA methylation signature was identified in individuals with Sotos syndrome (25), which differentiated individuals with molecularly confirmed Sotos syndrome from unaffected individuals, pathogenic NSD1 mutations from non-pathogenic variants, and individuals with Sotos syndrome from those with the distinct but closely related Weaver syndrome.

Similarly two phenotypically related disorders, KS and CHARGE syndrome, were shown to have similarly altered DNA methylation at individual common downstream target genes to account for some of the clinical overlap; overall however, they had mostly distinct, disease-specific DNA methylation signatures, which allowed differentiation between the conditions and between affected individuals and unaffected controls (26).

In the case of the X-linked disorder Claes–Jensen syndrome resulting from mutations in KDM5C, DNA methylation signatures were specific enough to differentiate between affected males, unaffected carrier females and unaffected non-carriers (27).

These DNA methylation changes likely result from a combination of direct and indirect effects of loss of individual components of the epigenetic machinery and should provide insight into pathogenesis.

Furthermore, their ability to characterize variants of uncertain significance in epigenetic machinery genes as pathogenic or non-pathogenic and to make diagnoses in previously unsolved cases illustrates diagnostic utility and has led to this DNA methylation array technology currently being offered as a clinically available diagnostic test (28).

Molecular pathogenesis, malleability and therapeutic considerations for the MDEMs. (Top panel) Epigenetic machinery maintains open (Gene 1; green triangles, acetylation; green hexagons, H3K4me3) and closed (Gene 2; red hexagons, H3K9me3 or H3K27me3; red lollipops, DNA methylation) chromatin states, which influence transcriptional programs in cells. Specifically, an expressed target of the writer (Gene 1) has associated writers of activating marks (green highlighters; HAT; HMT), erasers of silencing marks (erasers; KDMs, lysine demethylases), dual-function chromatin remodelers (bull dozer) and other readers (green glasses; bromodomain and chromodomain proteins). A silenced non-target of the writer (Gene 2) has associated writers of silencing marks (red highlighters; HMT; DNMT, DNA methyltransferases), erasers of activating marks (erasers; KDM, lysine demethylases; HDAC) and readers (red glasses; chromodomain proteins and methyl-CpG binding proteins). (Bottom panel) Upon loss of a writer of an open chromatin modification (broken highlighter) due to an MDEM, direct target genes may lose the relevant activating marks and transition to an abnormally closed chromatin state with associated DNA hypermethylation and aberrant gene silencing (Gene 1). Non-targets (Gene 2) may adopt an abnormal open chromatin state and become aberrantly expressed. Multiple potential therapeutic strategies exist to revert the abnormal chromatin and transcription states back to normal and are described in the text (arrow, inset box).
Molecular pathogenesis, malleability and therapeutic considerations for the MDEMs. (Top panel) Epigenetic machinery maintains open (Gene 1; green triangles, acetylation; green hexagons, H3K4me3) and closed (Gene 2; red hexagons, H3K9me3 or H3K27me3; red lollipops, DNA methylation) chromatin states, which influence transcriptional programs in cells. Specifically, an expressed target of the writer (Gene 1) has associated writers of activating marks (green highlighters; HAT; HMT), erasers of silencing marks (erasers; KDMs, lysine demethylases), dual-function chromatin remodelers (bull dozer) and other readers (green glasses; bromodomain and chromodomain proteins). A silenced non-target of the writer (Gene 2) has associated writers of silencing marks (red highlighters; HMT; DNMT, DNA methyltransferases), erasers of activating marks (erasers; KDM, lysine demethylases; HDAC) and readers (red glasses; chromodomain proteins and methyl-CpG binding proteins). (Bottom panel) Upon loss of a writer of an open chromatin modification (broken highlighter) due to an MDEM, direct target genes may lose the relevant activating marks and transition to an abnormally closed chromatin state with associated DNA hypermethylation and aberrant gene silencing (Gene 1). Non-targets (Gene 2) may adopt an abnormal open chromatin state and become aberrantly expressed. Multiple potential therapeutic strategies exist to revert the abnormal chromatin and transcription states back to normal and are described in the text (arrow, inset box).

Postnatal malleability of MDEMs

From a translational standpoint this group is interesting for several reasons.

Forty-three of the 70 disease-associated genes (61%) encode enzymes, which have traditionally been therapeutically targetable (29).

In addition, a large number of agents are available that can modify function of these enzymes (30).

Moreover, promising pre-clinical data available for multiple members of this group indicate that they may be treatable in postnatal life, including for Rett, Rubinstein-Taybi and Kabuki syndromes.

For Rett syndrome, conditional ablation of Mecp2 in mice led to a Rett-like phenotype, which was ameliorated upon genetic restoration of Mecp2 function (31).

In two distinct mouse models of the MDEM RTS resulting from deficiency of the histone acetyltransferase (HAT) CREBBP, long-term memory deficits were observed and subsequently improved upon treatment with HDAC inhibitors (32,33), suggesting postnatal reversibility of neurological phenotypes upon restoration of disrupted histone marks (in this case acetylation) using epigenetic therapies.

For KS1, heterozygous mutant mice exhibited visual-spatial learning deficits in association with defective hippocampal neurogenesis and loss of hippocampal H3K4 trimethylation (H3K4me3), and all were restored upon treatment with the HDAC inhibitor AR-42, which also increases H3K4 methylation levels (5).

In addition to pharmacological inhibition, therapy with a ketogenic diet—with effects due mostly to the HDAC properties of beta-hydroxybutyrate – led to similar therapeutic effects in KS1 mice (34).

These studies suggest that restoration of broad chromatin states, as opposed to simply restoring a single disrupted histone mark, is an effective additional treatment approach for MDEMs. Harnessing this malleability with epigenetic therapies like those above and others could lead to novel therapeutic approaches.

In that regard, many potential epigenetic, and non-epigenetic, therapeutic approaches exist for MDEMs (Fig. 2), though the above studies all used HDAC inhibitors (Fig. 2, therapy 6).

CRISPR gene editing to correct the mutation is a non-epigenetic potential future option for these and other genetic disorders that exhibit postnatal malleability (Fig. 2, therapy 1); however, off-target effects leading to mutations in unintended genomic targets remain a big concern (35).

The recent discovery that CRISPR-deadCas9 (CRISPR-dCAs9) linked to an epigenetic domain (EP300, KRAB) can open up or close chromatin at specific locations (36,37) is intriguing and may be particularly appealing as a therapeutic strategy because it can be targeted to specific sites but carries minimal risk of changing the germline (Fig. 2, therapy 2).

Another related but more directed approach is to specifically target one or more key downstream genes (Fig. 2, therapy 7); however, this approach may only ameliorate a subset of symptoms due to the many additional target genes involved. Regarding the broader group of epigenetic therapies, many HMT inhibitors targeting writers of repressive marks exist (Fig. 2, therapy 3), and relevant aberrant marks could include H3K27me3 or others.

Indeed, a variety of small molecule inhibitors of EZH2, the HMT writer of H3K27me3 and member of the polycomb repressive complex 2 (PRC2), exist (38) and could be utilized as a therapeutic approach alone or in combination with select targeting approaches.

In addition, chromodomain inhibitors (Fig. 2, therapy 4) have been developed, which can compete with PRC2 for recognition of H3K27me3 and de-repress genes (39). One of the best known and longest running epigenetic therapies are the DNA methyltransferase inhibitors (Fig. 2, therapy 5) (40).

These could be particularly and broadly useful in treating MDEMs, especially in light of the fact that many of these conditions have characteristic DNA methylation signatures. More specifically, this class of drugs might be particularly useful in treating microcephalic dwarfism due to DNMT3A mutations, as genome-wide aberrant DNA hypermethylation has been demonstrated (10).

In addition to the aforementioned single-therapy approaches, combination therapies could also be considered. For example, any particular epigenetic enzymatic domain could be combined with the CRISPR-dCAS9 approach, or alternatively, one could theoretically mix and match a variety of reader and enzymatic domains to achieve the desired specificity.

Many other potential therapies exist, including bromodomain inhibitors (41), HAT inhibitors (42), histone demethylase inhibitors (43) and others. The choice of therapy depends not only on the epigenetic mark that is directly disrupted, but also on downstream consequences, including alterations of other chromatin marks and of target gene expression.

The possibility exists that despite the diversity of directly altered epigenetic marks, multiple disorders could converge on one (or a few) particular distinct marks, namely DNA methylation or others. This may allow for treatment of multiple disorders with a single therapy and has important implications for therapeutic development, particularly in the case of rare diseases. Despite evidence of postnatal malleability in these conditions, one obstacle facing all therapies will be delivery to a relevant cell type at an appropriate developmental stage.

In summary, based on the availability of therapeutic approaches and ample evidence from pre-clinical studies of postnatal malleability and amelioration of neurological phenotypes, there is now more hope than ever that devastating neurodevelopmental disorders and associated ID, as well as other phenotypes like abnormal growth, may in fact be treatable.

Other disorders and looking ahead

Our list of epigenetic machinery genes and associated MDEMs has expanded immensely over the past 5 years but is likely still an underestimate due to ongoing discovery and objective limitations described above.

We have intentionally focused on factors that have strong evidence for direct involvement in determining epigenetic marks, but this stringency prohibited the inclusion of highly related disorders resulting from mutations in genes encoding other components of chromatin-modifying complexes that do not have one of the defined epigenetic machinery domains.

A case in point is the genetically heterogeneous Coffin–Sirus syndrome with many causative genes encoding protein components of the SWI/SNF (switch/sucrose non-fermenting) complex, which unequivocally cause disease but in many cases do not have one of the bioinformatically determined domains that we focused on here (44).

Additional examples are those resulting from mutations in histone genes (HIST1H1E, HIST1H4B and HIST3H3) (8,45) and the insulator CTCF (46). These genes and their associated disorders share many features with the disorders discussed above and should be thought of as members of the broader group but for simplicity were not included here.

Future discussion is needed within the translational genetics and epigenetics communities regarding how to precisely define this important and expanding group of disorders; improved understanding of disease pathogenesis may help us to elucidate the true role of epigenetics and chromatin states in health and disease.

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More information: A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and CGG expansions, American Journal of Human Genetics (2020). DOI: 10.1016/j.ajhg.2020.08.019www.cell.com/ajhg/fulltext/S0002-9297(20)30288-3

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