De Novo Mutations in CHD4 , an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms

Abstract

Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2β, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM_001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Siris syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification.

SMARCA4 inactivating mutations cause concomitant Coffin–Siris syndrome, microphthalmia and small‐cell carcinoma of the ovary hypercalcaemic type

“…Importantly, loss‐of‐function mutations of CHD7 are also associated with CHARGE syndrome (OMIM 214800), which is characterized, as in the case of CSS, by multiple congenital anomalies, including microphthalmia. Recently, de novo missense substitutions in the chromatin remodeller gene CHD4 have been associated with Sifrim–Hitz–Weiss syndrome (OMIM 617159), and mutations in the same positions have been reported in malignant tumours , thus supporting the hypothesis of common alterations shared between intellectual disability syndromes with distinctive dysmorphisms and cancer. Similarly to what has been reported for ARID1B ‐haploinsufficient individuals, the CSS phenotype in our patient was milder than in all previously reported cases with missense substitutions, which may exert a dominant‐negative effect on other complex proteins.…”

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

“…Our prior work revealed increased germline apoptosis in response to RNAi knockdown of several classes of chromatin remodelers, including the HDAC1 homolog hda-1 (Checchi and Engebrecht, 2011), which encodes a histone deacetylase that functions as part of a conserved, nucleosome remodeling and deacetylase (NuRD) complex (Passannante et al, 2010;Shi and Mello, 1998). In mammals, NuRD is essential for maintaining genomic stability, and dysregulation of its core catalytic components, the Mi2 subunits CHD4 and CHD3, has been implicated in several human cancers as well as in heritable developmental disabilities (Mills, 2017;Weiss et al, 2016 (Passannante et al, 2010). To investigate the role of both Mi2 subunits in maintaining genetic integrity, we assessed the consequences of CHD-3 and LET-418 (CHD4) loss both individually and in combination in the C. elegans germ line.…”

The Epilepsy Genetics Initiative: Systematic reanalysis of diagnostic exomes increases yield

“…This subject was initially reported to have a history of seizures, speech delay with regression, celiac disease, possible hearing loss, and a diagnosis of Landau‐Kleffner syndrome but was later reported to have normal hearing. CHD4 is associated with an autosomal dominant intellectual disability syndrome, with variable features and affected systems including cardiac, skeletal, and urogenital; additional findings can include hearing loss, macrocephaly, short stature, and nonspecific dysmorphic features . During reanalysis, EGI identified the same variant in three individuals in gnomAD.…”

“…CHD4 is associated with an autosomal dominant intellectual disability syndrome, with variable features and affected systems including cardiac, skeletal, and urogenital; additional findings can include hearing loss, macrocephaly, short stature, and nonspecific dysmorphic features. 17 During reanalysis, EGI identified the same variant in three individuals in gnomAD. An experienced clinical molecular geneticist on our team determined that the variant meets criteria for a VUS per ACMG guidelines for variant interpretation.…”