Pattern Recognition of Common Multiple Congenital Malformation Syndromes with Underlying Chromatinopathy

Abstract

Chromatinopathy is an emerging category of multiple malformation syndromes caused by disruption in global transcriptional regulation with imbalances in the chromatin states (i.e., open or closed chromatin). These syndromes are caused by pathogenic variants in genes coding for the writers, erasers, readers, and remodelers of the epigenetic machinery. Majority of these disorders (93%) show neurological dysfunction in the form of intellectual disability. Other overlapping features are growth abnormalities, limb deformities, and immune dysfunction. In this study, we describe a series of children with six common chromatinopathy syndromes with an aim to develop pattern recognition of this emerging category of multiple malformation syndromes

Introduction

Chromatinopathy is an emerging category of multiple congenital anomaly syndromes that are now understood to be caused by an underlying global transcriptional dysregulation due to pathogenic variants in the genes encoding proteins that are involved in epigenetic modification of chromatin. ¹ These proteins have been classified into what are called as writers, erasers, readers, and remodelers of the epigenetic machinery. ¹

Currently, 82 Mendelian disorders with pathogenic variants in 70 genes have been classified as disorders of epigenetic machinery. ² The majority of these disorders present clinically as multiple congenital anomaly syndromes and share certain overlapping features with neurological dysfunction in the form of intellectual disability (ID) being the most common overlapping feature. Other common shared features are growth disturbance, limb abnormalities, and immune dysfunction. We conducted a retrospective analysis to find multiple congenital anomalies with ID syndromes with molecularly proven and/or suspected underlying chromatinopathy, seen in our genetics clinic over a period of 3 years and present the details of six such children with underlying chromatinopathy, aiming to help the clinicians in pattern recognition of this emerging category of multiple congenital anomaly syndromes.

Materials and Methods

The records of patients presenting with suspected syndromic ID were analyzed. The criteria for considering chromatinopathy as an underlying cause of syndromic ID were (a) molecularly proven cases of Cornelia de Lange (CdLS), Rubeinstein-Taybi syndrome (RTS), Kabuki, or KBG syndrome (KBGS); (b) if the case record mentioned ID with growth abnormality (either prenatal in the form of low birth weight or postnatal) accompanied with limb abnormalities and/or hirsutism and a facial dysmorphic features resembling a well-defined chromatinopathy syndromes such as abnormality of the eyebrows or eyelids, short nose, long smooth philtrum. Wherever required, the patient's family was recontacted telephonically and requested to share a recent photograph of the patient for facial dysmorphology assessment. The information on anthropometry, associated systemic anomalies, relevant family history, and investigations were recorded on a case record form. Those cases with an alternate clinical and/or confirmed chromosomal or single gene diagnosis were excluded. Written informed consent was obtained from the parent/guardian for final publication of the patient's photograph.

Results

A total of 14 children with suspected or proven chromatinopathies were identified: four children with CdLS (two molecularly confirmed), two with RTS (one molecularly confirmed), one with KBGS (molecularly confirmed), four with Kabuki syndrome (one molecularly confirmed, other three with strong clinical possibility Supplementary Fig. S3 – S5 , available in the online version only), one with Coffin-Siris syndrome (CSS) (molecularly confirmed), one with Wiedemann-Steiner syndrome (WDST) (molecularly confirmed), and one child is strongly suspected to have a chromatinopathy; however, no specific chromatinopathy could be diagnosed clinically ( Supplementary Fig. S7 , available in the online version only). In 1/2 children with clinically suspected CdLS, an exome sequencing showed variants of unknown significance (VUS) ( Supplementary Fig. S1 , available in the online version only). Table 1 shows the clinical and molecular details of the confirmed cases. Supplementary data show the photographs and clinical features of the suspected cases. We describe in detail the phenotype of six children with molecularly confirmed chromatinopathy.

Table 1. Clinical and molecular details of the patients with confirmed chromatinopathies.

Sl. no	Age/sex	Clinical features	Molecular diagnosis	Final diagnosis
1A	7yr/M	GDD, hirsutism, brachycephaly, limb abnormalities, hypoplastic genitalia	NIPBL (ENST00000282516.13) (c.6893G > A) (pathogenic)	CdLS
1B.	4.5yr/F ( Fig. 1A, B )	GDD, FTT, arched eyebrows, smooth upper lip, thin upper lip vermilion, hirsutism, brachydactyly	NIPBL (ENST00000282516.8) (c.7235_7238delinsAA)(p.Ser2412Ter)	CdLS
2.	9mo/M ( Fig. 2A, B )	Broad thumbs, brachydactyly, downslant eyes, epicanthic folds, depressed nasal bridge, thin smooth upper lip, café-au-lait, glaucoma, epibulbar dermoid, mild developmental delay	CREBBP (c.886dupC) that resulted in a frameshift and premature truncation of the protein at codon 296	RTS
3.	5yr/F ( Fig. 3 )	Laterally sparse eyebrows, eversion of lateral third of lower eyelid, broad nasal tip, short columella	Heterozygous four base pair deletion exon 39 / KMT2D gene (c.11475_11478delACAG) /protein (p.Gln3826CysfsTer3)/ likely pathogenic	KS
4.	11mo/F ( Fig. 4 )	Small palpebral fissures, thin upper lip, hypertrichosis cubiti, puffy hands, hypotonia, GDD, FTT	KMT2A (ENST00000534358.1) (c.3464G > A) (p.Cys1155Tyr)	WDST
5.	3yr/M ( Fig. 5 )	GDD, synophrys, hirsutism, toe nail hypoplasia, scalp hypotrichosis, ASD, agenesis of corpus callosum	SMARCB1 (c.1096C > T) (p.Arg 366Cys)	CS
6.	13y/M ( Fig. 6 )	ID, hyperactivity, broad bushy eyebrows, short anteverted nostrils, smooth upper lip, hirsutism, prominent upper central incisors	ANKRD11 ( c.7814T > G) Likely pathogenic	KBG

Abbreviations: ASD, atrial septal defect; CdLS, Cornelia De Lange; CS, Coffin-Siris syndrome; FTT, failure to thrive; GDD, global developmental delay; ID, intellectual disability; KS Kabuki syndrome; RTS, Rubinstein-Taybi syndrome; WDST, Wiedemann-Steiner syndrome.

Patient 1: A four-and-a-half-year-old girl born with a low birth weight of 2 kg (–0.3 standard deviation [SD]) showed global developmental delay and failure to thrive. At the age of 4.5 years, her weight was 9.8 kg (–4.19 z-score), height was 88 cm (at −4.17 z-score), and head circumference was 42 cm (–8.4 z-score) as per Indian Academy of Pediatrics (IAP) growth charts. She had obvious facial dysmorphisms with arched eyebrows, synophrys, thin upper and lower lip vermillion, smooth upper lip, hirsutism, brachydactyly, and clinodactyly ( Fig. 1A, B ). Additionally, she had bilateral moderate-to-severe hearing loss and high myopia of −15.0 diopters in both eyes. Exome sequencing showed a de novo heterozygous indel (c.7235_7238delCTTTinsAA) in exon 42 of NIPBL gene (NM_133433.4) that resulted in a frameshift and premature truncation of protein at codon 2412 (p.Ser2412Ter). This variant is pathogenic as per American College of Medical Genetics (ACMG) classification. ³ The molecular finding was consistent with the clinical phenotype of CdLS.

Fig. 1.

( A ) Facial dysmorphism seen in girl with Cornelia De Lange syndrome—arched eyebrows, synophrys, thin upper and lower lip vermillion, smooth upper lip and hirsutism. ( B ) Hands show brachydactyly, clinodactyly.

Patient 2: A 9-month-old boy born at term with a birth weight of 2.8 kg (−1.18 SD). He was observed to have an epibulbar dermoid in the left eye at birth. At the age of 5 months, glaucoma was diagnosed in the right eye. Developmental milestones appeared slightly delayed with child being able to sit without support only momentarily at the age of 9 months. On examination, he had large cornea (right side), left epibulbar dermoid, mild downslanting of eyes, epicanthus, thin upper lip vermillion, broad thumbs, and great toes as well as bilateral cryptorchidism ( Fig. 2A, B ). A café au lait spot was noted on left upper arm and Mongolian spots on buttocks and upper back. Multiplex ligation probe amplification for common chromosomal microdeletion syndromes showed no copy number variants. However, exome sequencing identified a heterozygous one base pair duplication (c.886dupC) in exon 3 of CREBBP that resulted in a frameshift and premature truncation of the protein at codon 296 (p.Gln296ProfsTer54). The aberrant transcript will likely be targeted by the nonsense-mediated mRNA decay mechanism . This variant has been reported as pathogenic in the ClinVar database with accession ID (RCV000729939).

Fig. 2.

( A ) Photograph of child with Rubinstein-Taybi syndrome illustrating large cornea, left eye epibulbar dermoid, mild downslanting of eyes, epicanthus and thin upper lip vermillion. ( B ) Broad thumbs.

Patient 3: A 13-year-old boy presented with ID and behavioral problems in form of hyperactivity. He was born out of a twin gestation at 32 weeks with a birth weight of 1 kg (–2.03 SD). He underwent surgical correction for bilateral cryptorchidism at the age of 5 years. On examination, his weight was 38 kg, height was 154 cm, and the occipitofrontal circumference (OFC) was 50 cm that corresponded to −0.43, 0.26 and −3.2 z-score for age. He had coarse facial features such as hypertelorism, low anterior hair line, synophrys, broad bushy eyebrows, prominent nasal bridge, thick alae nasi, long smooth philtrum, prominent upper central incisors, and macrodontia ( Fig. 6 ). Mild cerebral atrophy was noted on neuroimaging. Exome sequencing was carried out and revealed a heterozygous variant (c.7814T > G; p.Leu2605Arg) in the ANKRD11 gene (NM_001256183.2). The variant was classified as likely pathogenic according to ACMG guidelines. ³ In the ClinVar database, this variant has been reported as pathogenic (RCV000493206) and likely pathogenic (RCV001251206) in the context of ID.

Fig. 6.

Photograph shows boy with KBG syndrome with coarse facial features, hypertelorism, low anterior hair line, synophrys, broad bushy eyebrows, prominent nasal bridge, thick alae nasi, and long smooth philtrum.

Patient 4: A 5-year-old girl, first born to non-consanguineous parents with birth weight of 2.6 kg (−1.82 SD). She was operated for anovaginal fistula at the age of 8 months. At the age of 5 years, she had an episode of generalized tonic–clonic seizures and was started on antiepileptic drugs. Motor and language delay was present. Her weight, height, and OFC were 12.8 kg, 96.5 cm, and 46 cm, which corresponded to −3, −2.9, and −4.1 z-scores, respectively, as per IAP growth charts. Facial features showed sparse eyebrows, prominent eyelashes, eversion of lateral third of lower eyelid, depressed nasal bridge, depressed nasal tip with short columella, and anteverted prominent ears ( Fig. 3 ). Exome sequencing revealed a heterozygous four base pair deletion (c.11475_11478delACAG) in exon 39 of the KMT2D gene (NM_003482.4) that resulted in a frameshift and premature truncation of protein (p.Gln3826CysfsTer3). This variant was classified as likely pathogenic according to ACMG guidelines ³ and has previously been reported as pathogenic for Kabuki syndrome-1 in the ClinVar database (RCV000416323).

Fig. 3.

Facial features of girl with Kabuki syndrome show sparse eyebrows, prominent eyelashes, eversion of lateral third of lower eyelid, depressed nasal bridge, depressed nasal tip with short columella, and anteverted prominent ears.

Patient 5: An 11-month-old girl born out of nonconsanguineous marriage at full term with a birth weight of 2.140 kg (−3.07 SD). At the age of 3 months, his weight was 3.3 kg (−3.6 z-scores) and OFC was 34.5 cm (−3.9 z-scores). Facies appeared dysmorphic with bushy eyebrows with medial flare, synophrys, hypertelorism, bilateral small palpebral fissures, upturned nasal tip, and thin smooth upper lip with facial hair. Hands appeared to be puffy with tapering fingers ( Fig. 4 ). Mild axial hypotonia and head lag were observed in infancy; however, nerve conduction studies and neuroimaging were normal. Chromosomal microarray revealed two VUS copy number variants. At the age of 11 months, her OFC was at −4.6 z-score, weight for age −3.4 z-scores, and length was at −5.17 z-score. Excessive hair growth on face, back, and elbows was observed. Parents complained of excessive irritability in the child. Global developmental delay was evident. Exome sequencing revealed a heterozygous variant (c.3464G > A; p.Cys1155Tyr) in exon 5 of KMT2A gene, suggestive of WDST. The identified variant was not detected in parental samples. This variant was classified as pathogenic for WDST syndrome according to ACMG guidelines. In the ClinVar database, this variant has been reported as pathogenic (RCV000414422) and pathogenic/likely pathogenic (RCV000824854) for WDST.

Fig. 4.

Photograph of girl with Wiedemann-Steiner syndrome who appears dysmorphic with bushy eyebrows with medial flare, synophrys, hypertelorism, bilateral small palpebral fissures, upturned nasal tip, thin smooth upper lip with facial hair.

Patient 6: A 3-year-old male child patient was born at term to a nonconsanguineous couple with birth weight of 2.2 kg (−3.24 SD) with smooth neonatal period. The child was noted to have recurrent respiratory tract infections with episodes of acute diarrhea, poor growth, and developmental delay at the age of 8 months. At the age of 3 years, excessive hair growth over face and shoulder was noticed. Clinical evaluation showed weight and height at −2.4 and −2 z-scores, respectively. His OFC was at +0.55 z-score. The child had mild coarse facies, scalp hypotrichosis, thick lengthy eyebrows, thin upper vermilion, thick lower vermilion, fully everted lower lip, hypertrichosis extending along the mandible, neck and shoulders, and hypoplastic nails in all the digits of feet ( Fig. 5 ). He showed hyperactivity with moderate ID. Echocardiography revealed presence of a 5 mm ostium secundum atrial septal defect. Brain MRI showed poorly visualized rostrum of corpus callosum. Karyotyping and chromosomal microarray were normal. Exome sequencing detected a heterozygous missense variant (NM_003073.4: c.1096C > T; p.Arg 366Cys) in exon 8 of SMARCB1 gene correlating with CSS3. Sanger sequencing of the child and parents confirmed that this variant is de novo . The identified variant was classified as pathogenic according to the ACMG guidelines. ³ This variant has been reported in the ClinVar database as pathogenic (RCV000255465) and likely pathogenic (RCV001782753) for CSS.

Fig. 5.

Hypoplastic nails in all the digits of feet seen in a child with Coffin-Siris syndrome.

Discussion

The chromatin consists of the DNA wrapped over the histone proteins that is the packaged form of DNA. The successful gene expression, however, requires access of the transcriptional machinery to the target genes. Genes can be expressed by loosening/opening up of the chromatin or transcriptionally silenced by condensing/closed state of chromatin. Human embryonic development shows temporal expression of many genes and a dysregulation in chromatin state and transcription of widely expressed genes can be anticipated to cause developmental syndromes. ⁴

The regulation of chromatin states involves a number of proteins that have been grouped as writers, erasers, readers, and remodelers of the epigenetic machinery. ² The writers and erasers consist of enzymes causing chemical posttranslational modification of histones and DNA (in the form of acetylation/deacetylation and methylation/demethylation). The reader proteins read or recognize these posttranslational marks and finally the remodeler proteins modulate the nucleosome (DNA + Protein) sliding or conformational changes, thus overall regulating the balance between the open and the closed chromatin states of a cell. In general, acetylation of histone is associated with active gene expression and methylation of the DNA with gene repression. The disturbances in the epigenetic mechanisms of the syndromes discussed here have been highlighted in Table 2 .

Table 2. Typical and overlapping features of some common chromatinopathy syndromes.

	CdLS	RTS	WDST	KBG	Kabuki	Coffin-Siris syndrome
Gene(s)	NIPBL, SMC1A, SMC3, HDAC8, RAD21	CBP , EP300	KMT2A	ANKRD11	KMT2D, KDM6A	ARID1A / B , SMARCA4B1/C2/D1/E1, SOX4/11, DPF2, BICRA
Disturbance in epigenetic function	Chromatin remodeling and histone deacetylation (HDAC8)	Histone acetylation	Histone methylation	Histone deacetylation	Histone methylation and demethylation	Chromatin remodeling
Growth	Pre-and postnatal retardation	Postnatal growth retardation	Postnatal growth retardation, short stature	Height <10 th centile	Short stature	Postnatal growth retardation
Head size	Micro/brachycephaly	–	–	–	Microcephaly	–
Eyes
Eyebrows	Arched	Arched	Arched, broad	Bushy, wide	Arched, broad, laterally sparse	Bushy eyebrows
Synophrys	+	–	+	+	–	+
Palpebral fissure (PF)	–	Downslanted PF	Vertically narrow PF	–	Long PF, eversion of lateral third of lower eyelid	–
Hypertelorism	–	–	–	+	–	–
Nose
Nasal ridge	Short nose	Convex	–	–	–	–
Nasal bridge	–	–	Broad	Prominent	–	–
Nasal tip	Upturned	–	Bulbous	Bulbous	Depressed	–
Columella	–	Overhanging beyond alae nasi	–	–	Short	–
Alae nasi	Anteverted	–	–	–	–	–
Upper lip
Philtrum	Long smooth	–	Long smooth	Long smooth	–	–
Vermillion	Thin	–	Thin	Thin	–	Lower lip thick, everted
Hirsutism	+	–	+	+	+	+
Generalized/localized hypertrichosis	+	–	+	+	+	+
Skeletal/limb anomalies	Severe to mild (phocomelia to short index finger/clinodactyly)	Broad thumb/Hallux	Puffy hands and tapering fingers or fleshy hands	Brachydactyly	Persistent fingertip pads, brachydactyly	Hypoplasia of nails/digits (most often the fifth)
Unique feature	–	Grimacing smile	–	Macrodontia	Lateral abnormalities in eye	–
Others	Congenital diaphragmatic hernia	Cryptorchidism	Immunodeficiency	Cryptorchidism, seizures, palate abnormality, autism, large AF or delayed closure	Prominent cupped ears, Immunodeficiency	–

Cornelia De Lange Syndrome— A Cohesinopathy

CdLS is an ID syndrome with characteristic features being a distinctive facies, pre- and postnatal growth retardation, and limb anomalies. The classical facies consist of arched eyebrows with synophrys, short nasal bridge with anteverted nares smooth long philtrum, and thin upper lip ( Fig. 1A ). Facial phenotype of individuals can range from classical (easily recognizable) to nonclassical type, which might be suspected to be CdLS but better reversed phenotype after molecular testing. Limb anomalies may range from severe reduction defects and oligodactyly to small hands and mild phalangeal abnormalities at the milder end of the spectrum ( Fig. 1B ). An international consensus scoring system now exists to classify a phenotype as classic or nonclassical CdLS. ⁵ In our study, 2/4 children had classical CdLS phenotype along with molecular confirmation (patient 1 and 2 in Table 1 ), one had the nonclassical CdLS with 9 points and one had the classical CdLS with clinical score of 11 points ( Supplementary Figs. S1 and S2 , respectively, available in the online version only).

The CdLS spectrum is associated with heterozygous pathogenic variants in the genes encoding for proteins of cohesion complex. Presently, there are five genes ( NIPBL, SMC1A, SMC3, HDAC8, and RAD21 ) known to be associated with the CdLS spectrum. The cohesion complex has multiple functions in a cell including chromatin modification and transcriptional regulation. The animal models and the patient derived cell lines have shown disturbances in normal role of transcriptional regulation by cohesion proteins, which may explain the pathophysiological mechanism of CdLS. It is proposed that the cohesion proteins by virtue of their ring conformation cause DNA looping and allow physical interactions between the promoters of the target genes and their regulatory regions. NIPBL is involved in loading of the cohesion ring onto the genomic region; SMC3 gets acetylated once loaded onto genome followed by deacetylation by HDAC8. HDAC8 thus causes dissolution of procohesive elements and allows recycling “of refreshed” cohesion for next cell cycle. Besides this, the cohesion proteins directly interact with RNA polymerases II, which initiate transcription. ⁴

Rubinstein-Taybi Syndrome: A Disorder of the Writer of the Epigenetic Machinery

This syndrome is characterized by distinct facies with broad thumbs/hallux, postnatal growth retardation along with ID. The most distinctive facial features are convex nasal ridge and overhanging columella apart from downslanting palpebral fissures and arched eyebrows. However, if the facies are not typical, broad thumb/hallux is a good sign to suspect this syndrome such as in the child presented above ( Fig. 2A, B ).

CBP and EP300 (CREB-binding protein and p300) are the two genes associated with this syndrome. The protein products of CBP and EP300 are structurally similar and both function as transcriptional coactivators and histone acetyltransferases in a number of cell signaling pathways. Therefore, a global chromatin dysregulation and transcriptional disturbance are considered as the molecular mechanism behind this syndrome. In 50 to 60% of clinically diagnosed RTS cases, heterozygous pathogenic variants including deletion/duplications were seen in CBP gene, while EP300 pathogenic variants account for 8 to 10% of cases. EP300 mutations were more often but not necessarily associated with milder phenotype.

KBG Syndrome: A Disorder of the Eraser of the Epigenetic Machinery

This syndrome is characterized by macrodontia, facies comprising triangular face with broad and bushy eyebrows, prominent nasal bridge, and long philtrum with thin vermillion. Brachycephaly along with ID has also been reported in this syndrome. The facial gestalt can be unclear with a variable presentation making the diagnosis clinically difficult especially in infants and young children. Different authors have suggested diagnostic criteria. ^{6 7}

The gene associated with this syndrome is the ANKRD11 that en codes for an ankyrin repeat protein 11, which is widely expressed and has been implicated in transcriptional silencing by recruitment of histone deacetylases such as HDAC3, 4 and 5 as well as transcriptional activation through the protein's activating domain. Individuals with overlapping phenotypes of KBGS and CdLS have been reported in literature. ⁸ It is hypothesized that as both ANKRD11 and Cohesion complex are involved in regulating gene expression, there might be dysregulation of some functionally interconnected genes due to the deficiency of either ANKRD11 or cohesion complex leading to overlapping phenotypes. ¹⁶

Kabuki Syndrome (KS): A Disorder of the Writer or Eraser of the Epigenetic Machinery

KS is characterized by distinct facial dysmorphism, growth retardation, ID, and a spectrum of congenital anomalies. International consensus diagnostic criteria now exist to facilitate the diagnosis of KS. ⁹

The typical dysmorphic features consist of long palpebral fissures with eversion of the lateral third of the lower eyelid, arched and broad eyebrows with the lateral third displaying notching or sparseness, short columella with depressed nasal tip, and large prominent or cupped ear ( Fig. 3 ). It is said that the facial features are most easily recognized between 3 and 12 years of age as they are difficult to define in infants and by adulthood the eversion of the eyelid may resolve. ⁹ The limb anomalies in this syndrome consist of abnormal dermatoglyphics, persistent fetal finger pads, and brachydactyly. As in WDST, KS also shows predisposition to several immunological abnormalities with hypogammaglobulinemia and susceptibility to infection as well as increased risk of autoimmune diseases. ¹⁰

Most KS patients (50–90%) have pathogenic variants in KMT2D , while in around 5% KMD6A has been found to be mutated in KS. KMT2D is a lysine (K)-specific histone methyltransferase (2 and D denote the family KMT2 A-E), whereas KMD6A is a lysine (K)-specific histone demethylase 6A. The names of these genes/enzymes suggest they have complementary functions; however, the loss of function of either has clinically similar effects as explained below.

KMT2D causes methylation of the histone H3K4, which is associated with an open chromatin state allowing several transcription factors to access the promoter regions or transcriptional start sites. The methylated H3K4 (H3K4Me) is considered as a genome-wide marker of gene activation. However, KDM6A demethylates H3K27, a histone that is when methylated causes transcriptional silencing. ³⁰ Thus, the loss of function of either KMT2D or KDM6A would interfere with the upregulation of several target genes. Loss of function animal models of these genes has been shown to effect craniofacial, heart, and neural development. ^{1 11}

Wiedemann–Steiner Syndrome

The major clinical features of this syndrome include a facial gestalt comprising of synophrys with broad, arched eyebrows reminiscent of CdLS, long and vertically narrow palpebral fissures, wide nasal bridge with broad and bulbous tip, long philtrum, and thin vermillion. The hands usually appear puffy and small. Hypertrichosis of the elbows is seen in around 60% of the patients. There may be associated generalized or localized hypertrichosis. Hypotonia during the neonatal period was noticed in half of the patients. There are reports of immunodeficiency with this syndrome and evaluation of the immunological profile is warranted in this syndrome. ¹²

KMT2A , the gene associated with WDST, is a lysine-specific methyltransferase responsible for methylating the histone H3 (K4H3me). Its functional effect is to open the chromatin causing transcription of multiple target genes. ²⁸

Coffin-Siris Syndrome: A Disorder of the Chromatin Remodeler

CSS is a clinically heterogenous syndrome with the main features such as hypoplasia of nails/digits (most often the fifth), sparse scalp hair, bushy eyebrows, wide mouth with prominent or thick lips especially the lower lip, body hirsutism as well as growth, and development retardation. Here again, the facial features may not be apparent until childhood.

This syndrome is caused by mutations in the genes encoding for proteins of the BAF complex, which in turn belong to the SWI/SNF chromatin remodeler complex family. The proteins of the BAF complex possess ability to change the chromatin conformation and have been found to bind to regulatory regions of the genome (i.e., promoters or enhancers). ²⁹ The SWI/SNF and the cohesion complex have overlapping functions of chromatin remodeling and epigenetic modifications possibly explaining the phenotypic overlap between CSS and CdLS.

Overlapping Phenotypes: From Cohesinopathies and BAFopathies to Chromatinopathies

With the increasing use of next-generation sequencing in the past few years, several cases of less typical and overlapping phenotypes of disorders such as CdLS, RTS, KBG, CSS, and others have been diagnosed. For example, Di Fede et al reported six patients with the initial clinical diagnosis of RTS were found to carry pathogenic variations in KMT2A . ¹³ The authors reported that in these patients have overlapped clinical pictures with RTS such as columella below alae nasi, broad thumbs/hallux, and ptosis and WDST such as broad nasal tip, narrow palpebral fissures, and hirsutism. There are other reports of KMT2A variants that were identified in patients with clinical diagnosis of CSS, CdLS, Kabuki syndrome, and RTS. ^{14 15 16 17 18} Similarly, overlapping phenotypes between CdLS and RTS, ¹⁹ CdLS and KBG, ⁸ CdlS and both RTS and KBG, ²⁰ KBG and CSS ²¹ have been reported. The reader may refer to the photographs and reports of these patients to understand the pattern of clinical phenotypes, which are increasingly being clubbed together as chromatinopathies due to the realization of disturbance in the epigenetic machinery and chromatin states, which seems a common underlying genetic cause for such phenotypes. Avagliano et al reported that chromatinopathies can be considered as a part of or an endophenotype of a larger disease family sharing different clinical features. ²² Table 2 shows the typical and overlapped clinical features of the syndromes reported in this series.

Customized next-generation sequencing panels with genes associated with chromatinopathies when applied to heterogenous cohort of patients with clinical diagnosis or suspicion of chromatinopathies gave a diagnostic yield as high as 32% ²³ with many patients receiving alternate diagnosis after sequencing and clinical re-evaluation. Furthermore, many of chromatinopathies have been found to have their own specific global methylation pattern or episignatures. These episignatures can be used for reclassification of VUS identified in the corresponding syndrome by next generation sequencing. ²⁴

Besides the phenotypic overlap, another prominent feature shared between chromatinopathies and other mendelian disorders of epigenetic machinery is the dominant mode of inheritance, which accounts for around 90% of the reported cases. ² It is proposed that since the epigenetic modifications are made by multiprotein complexes, even a change in a single component can disrupt the normal complex formation and thereby its function.

This group of disorders has potential for postnatal malleability. Mouse models of RTS and Kabuki syndrome have shown response in hippocampal memory defects by histone deacetylase inhibitors. ^{25 26 27} In view of these observations, it has been proposed that in future the epigenetic ID disorders might become a treatable group of neurodevelopmental disorders.

Conclusion

An insight into the molecular links of certain multiple malformation syndromes as well as increasing use of next-generation sequencing in clinical practice has led to appearance of this group of chromatinopathies. This has led to a recognition pattern for some common classical chromatinopathies. It is believed that many atypical or less typical phenotypes of classical chromatinopathy syndromes are likely to be discovered in future.