Hum Mutat. 2026 Feb 25;2026:3575977. doi: 10.1155/humu/3575977. eCollection 2026.
ABSTRACT
Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a critical ATP-dependent chromatin remodeler that plays fundamental roles in transcriptional repression, DNA damage repair, and lineage specification, making it indispensable for cardiovascular development and function. Pathogenic CHD4 mutations are linked to syndromic and nonsyndromic conditions, often presenting with severe cardiac and vascular anomalies. However, most of these mutations are unique and nonrecurrent, complicating variant classification. In this study, we establish a connection between recent advances in CHD4 structure and function and 36 pathogenic CHD4 mutations associated with rare diseases, including Sifrim-Hitz-Weiss syndrome, moyamoya angiopathy, and childhood idiopathic epilepsy with sinus arrhythmia, all of which exhibited cardiomyopathy, congenital heart defects, and/or vascular abnormalities. Among these mutations, 33 were missense variants, one was an in-frame small insertion, one, an in-frame small deletion, and one, a splice-site variant. Variants were classified according to the ACMG guidelines and subsequent refinements, integrating clinical, functional, population, and in silico (REVEL-based PP3/BP4) evidence, and cross-referenced with the ClinVar database to prioritize candidates for further association and functional studies. We classified the missense variants as follows: seven as pathogenic (P), nineteen as likely pathogenic (LP), one as likely benign (LB), and six as variants of uncertain significance (VUS). The splice-site variant was predicted to cause nonsense-mediated decay and reduced CHD4 expression, whereas the structural variants were predicted to exert moderate effects on protein function. LP/P variants associated with congenital heart defects were significantly enriched within the ATPase/helicase domain (p = 0.027), suggesting impairing ATPase motor activity. Nevertheless, several severe heart malformations, including tetralogy of Fallot were linked to pathogenic or LP variants, such as C467Y (plant homeodomain [PHD]), M202I (high-mobility group [HMG]), and Y1345D (C-terminal domain). In contrast, other variants located in the N- and C-terminal regions were more often associated with vascular phenotypes, suggesting domain-specific roles of CHD4 in cardiovascular disease. These findings establish CHD4 as a key regulator of cardiovascular pathophysiology, though a clear genotype-phenotype correlation remains elusive. Further functional validation is essential to elucidate CHD4's molecular mechanisms, aiding in diagnostic and therapeutic developments.
PMID:41756679 | PMC:PMC12935301 | DOI:10.1155/humu/3575977