The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype–phenotype correlations, and molecular basis

Purpose: Sifrim–Hitz–Weiss syndrome (SIHIWES) is a recently describedmultisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated theclinical spectrum of the disorder, genotype–phenotype correlations, and theeffect of different missense variants on CHD4 function. Methods: We collected clinical and molecular data from 32 individuals withmostly de novo variants in CHD4, identifiedthrough next-generation sequencing. We performed adenosine triphosphate (ATP)hydrolysis and nucleosome remodeling assays on variants from five different CHD4domains. Results: The majority of participants had global developmental delay, mild tomoderate intellectual disability, brain anomalies, congenital heart defects, anddysmorphic features. Macrocephaly was a frequent but not universal finding.Additional common abnormalities included hypogonadism in males, skeletal andlimb anomalies, hearing impairment, and ophthalmic abnormalities. The majorityof variants were nontruncating and affected the SNF2-like region of the protein.We did not identify genotype–phenotype correlations based on the type orlocation of variants. Alterations in ATP hydrolysis and chromatin remodelingactivities were observed in variants from different domains. Conclusion: The CHD4-related syndrome is a multisystemic neurodevelopmentaldisorder. Missense substitutions in different protein domains alter CHD4function in a variant-specific manner, but result in a similar phenotype inhumans.