CHD7 – CHARGE Syndrome

CHARGE syndrome is an autosomal dominant multiple‐malformation disorder caused by heterozygous loss‐of‐function mutations in CHD7. Sequencing of 110 unrelated individuals clinically diagnosed with CHARGE revealed CHD7 mutations in 64 (58%) cases, including nonsense, frameshift, splice‐site, and missense variants ([PMID:16400610]). Familial segregation in two independent pedigrees, including proven de novo and germline mosaicism, confirms autosomal dominant inheritance with variable expressivity ([PMID:19475719]). Functional assays demonstrate that patient‐derived CHD7 variants disrupt ATP‐dependent nucleosome remodeling activity—mutations upstream of amino acid 1899 yield hypomorphic proteins, while chromodomain missense changes abolish CHD7–CHD8 interaction ([PMID:23134727]). In mouse and zebrafish models, Chd7 deficiency recapitulates key CHARGE features and can be mitigated by modulating p53 activity or retinoic acid signaling, underscoring a mechanistic link between CHD7 chromatin remodeling and developmental pathways ([PMID:25119037]; [PMID:24026680]). Clinically, CHD7 mutation‐positive patients present with ocular coloboma, choanal atresia, semicircular canal aplasia, hearing loss, congenital heart defects, genital hypoplasia, and growth retardation, meeting established diagnostic criteria. Rigorous genetic testing—including sequencing, deletion/duplication analysis, and splicing assays for cryptic intronic variants—is essential for definitive diagnosis and genetic counseling ([PMID:26551301]).

Key Take-home: CHD7 genetic testing has definitive clinical validity for diagnosing CHARGE syndrome, guiding surveillance and family counseling.

References

• American Journal of Human Genetics | 2006 | Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation PMID:16400610
• Clinical Genetics | 2009 | Proven germline mosaicism in a father of two children with CHARGE syndrome PMID:19475719
• Proceedings of the National Academy of Sciences of the United States of America | 2012 | Chromatin remodeling by the CHD7 protein is impaired by mutations that cause human developmental disorders PMID:23134727
• Nature | 2014 | Inappropriate p53 activation during development induces features of CHARGE syndrome PMID:25119037
• Human Molecular Genetics | 2014 | CHD7 and retinoic acid signaling cooperate to regulate neural stem cell and inner ear development in mouse models of CHARGE syndrome PMID:24026680
• Gene | 2016 | Revealing the function of a novel splice-site mutation of CHD7 in CHARGE syndrome PMID:26551301

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