Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

Abstract

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic-clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

Fig. 1

Family trees of the inherited mutations. In family 1, Individual III-3 corresponds to Patient 1. In family 2, Individual III-1 corresponds to Patient 4. In family 3, Individual III-1 corresponds to Patient 6. The variants in CHD5 identified in these three families are associated with incomplete penetrance and variable expressivity

Fig. 2

Distribution of the CHD5 variants based on position and conservation of the affected amino acids. a Schematic representation of the CHD5 protein and its domains, with position of the identified mutations relative to exon and domain distribution. The CHDNT domain is indicated in yellow, the PHD domains in red, the Chd domains in green, the helicase domains in light blue, the DUFs domains in purple, and the CHDCT2 domain in lilac. Inherited variants are indicated in blue and de novo variants in black. Putative loss-of-function variants are indicated with a triangle, likely pathogenic missense substitutions with a filled circle and the VUS with an empty circle. b Comparison of the distribution of the variants identified in our cohort with the synonymous and missense variants reported in gnomAD, with relative position of each affected CHD5 residue across the protein domains. c Comparison of a portion of the highly conserved C-terminal Helicase domain among yeast SNF2 (black) and human CHD3 (red), CHD4 (green), and CHD5 (blue). Pathogenic missense substitutions altering residues in this domain are indicated with the color corresponding to the CHD protein where the variant was identified. The amino acids altered by the substitutions are indicated with a square whose color corresponds to the CHD protein where the variant was identified

Fig. 3

Facial profiles of patients with CHD5 variants. a–c Patient 1 age 6 months. d, e Patient 2 age 11 years 4 months. f Patient 4 age 1 year. g, h Patient 7 age 24 years. i, j Patient 10 age 3 (i) and 5 years (j). k–n Patient 13 age 9 months (k), 9 years (l) and 22 years (m, n). o, p Patient 14 age 3 years six months (o) and 6 years (p). Facial dysmorphism was related to craniosynostosis in Patients 1 and 4. Other patients displayed subtle facial features, such as high forehead, but no consistent facial dysmorphism emerges from the whole panel