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Sifrim-Hitz-Weiss syndrome is an autosomal dominant multisystemic neurodevelopmental disorder characterized by global developmental delay, congenital heart defects, macrocephaly, hypogonadism, hearing impairment, and distinct facial dysmorphisms. The disorder is caused by heterozygous de novo variants in CHD4, encoding an ATP-dependent chromatin remodeler integral to transcriptional regulation and DNA repair. Detailed genotype-phenotype investigations have delineated a consistent clinical spectrum across independent cohorts.
Genetic evidence includes de novo CHD4 variants in 32 unrelated probands (PMID:31388190), 39 additional individuals in a DNA methylation episignature study (PMID:39824190), and a novel frameshift in a single proband (PMID:36672520). The majority of these 72 probands harbored nontruncating missense substitutions clustering within the SNF2-like ATPase/helicase domain, with one frameshift variant illustrating phenotypic concordance.
Variants are predominantly missense; the canonical example is c.3778C>T (p.Arg1260Cys), which impairs ATP hydrolysis and nucleosome remodeling activity. Truncating variants have been reported but their pathogenic contribution remains less clear. All variants arose de novo, with no evidence of transmission in family members, consistent with a dominant mechanism.
Functional studies demonstrate that CHD4 missense substitutions reduce ATPase activity and nucleosome remodeling in vitro (PMID:31388190). DNA methylation profiling revealed a sensitive episignature specific to pathogenic ATPase/helicase domain variants, distinguishing clinical and molecular subtypes (PMID:39824190). A CRISPR-engineered homozygous p.Gly1003Asp hESC line retains pluripotency and will enable mechanistic modeling of SIHIWES in vitro.
The cumulative evidence supports a definitive gene-disease association for CHD4 and Sifrim-Hitz-Weiss syndrome, with strong genetic and moderate experimental concordance. Additional functional work, including in vivo models and rescue assays, could further elucidate mechanistic pathways. Key Take-home: CHD4 de novo missense variants in the ATPase/helicase domain reliably diagnose SIHIWES and guide genetic counseling.
Gene–Disease AssociationDefinitiveDe novo variants in 72 probands from three independent cohorts with concordant phenotype and functional data Genetic EvidenceStrong72 de novo variants in unrelated probands across multiple studies; meets high-confidence de novo criteria Functional EvidenceModerateIn vitro assays demonstrate altered ATP hydrolysis and nucleosome remodeling concordant with clinical phenotype; DNA methylation episignature differentiates pathogenic variants |