CHD7 – Kallmann Syndrome

CHD7 encodes a chromatin-remodeling ATP-dependent helicase classically mutated in CHARGE syndrome and has been implicated in the pathogenesis of Kallmann syndrome (KS), a form of congenital hypogonadotropic hypogonadism with anosmia. Initial mutational screening of CHD7 in 101 idiopathic hypogonadotropic hypogonadism and KS patients identified seven heterozygous CHD7 variants, including three in KS patients without typical CHARGE features ([PMID:18834967]). Subsequent analysis of 56 KS or normosmic IHH patients revealed three additional CHD7 mutations with retrospective evidence of familial segregation in five relatives showing partial CHARGE spectrum features ([PMID:19021638]). A Dutch cohort of 36 well-characterized KS patients without KAL1 mutations yielded four CHD7 deleterious variants, each associated with at least two additional CHARGE-related anomalies ([PMID:22399515]).

Case reports further expand the spectrum: a 19-year-old woman with KS and CHARGE features carried a novel frameshift c.6405_6406delAG (p.Ala2137ArgfsTer2) confirmed de novo by parental testing ([PMID:28609304]), and a pediatric KS case with incomplete CHARGE traits harbored c.6571G>A (p.Glu2191Lys) demonstrating reduced penetrance ([PMID:29979396]). These studies establish an autosomal dominant inheritance pattern with variable expressivity.

Functional assays corroborate genetic findings. Minigene splicing experiments on the V1452L variant showed aberrant exon skipping and in-frame deletion disrupting the helicase domain, leading to reclassification as likely pathogenic ([PMID:39596130]). Zebrafish otolith assays of patient-derived CHD7 alleles demonstrated loss of function in 75% of variants tested ([PMID:25472840]), and in vitro remodeling assays revealed that mutations truncate or abrogate nucleosome remodeling activity of CHD7 ([PMID:23134727]).

Conflicting evidence is limited to observations of incomplete penetrance in family members carrying CHD7 missense alleles without overt KS or CHARGE phenotypes, underscoring variable expressivity and the need for detailed phenotyping even in asymptomatic carriers.

Together, genetic and experimental data across multiple independent cohorts and model systems support a Strong clinical validity for CHD7 in KS. CHD7 sequencing should be prioritized in KS patients, particularly those with hearing loss, clefting, or semicircular canal anomalies. Key take-home: CHD7 pathogenic variants cause KS in an autosomal dominant manner with variable expressivity, guiding diagnosis and genetic counseling.

References

• American journal of human genetics • 2008 • Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. PMID:18834967
• Clinical genetics • 2009 • CHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndrome. PMID:19021638
• The Journal of clinical endocrinology and metabolism • 2012 • The results of CHD7 analysis in clinically well-characterized patients with Kallmann syndrome. PMID:22399515
• Otology & neurotology • 2017 • Suprameatal Cochlear Implantation in a CHARGE Patient With a Novel CHD7 Variant and KALLMANN Syndrome Phenotype: A Case Report. PMID:28609304
• Medicine • 2018 • Clinical data and genetic mutation in Kallmann syndrome with CHARGE syndrome: Case report and pedigree analysis. PMID:29979396
• International journal of molecular sciences • 2024 • Kallmann Syndrome: Functional Analysis of a CHD7 Missense Variant Shows Aberrant RNA Splicing. PMID:39596130
• Proceedings of the National Academy of Sciences of the United States of America • 2014 • Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency. PMID:25472840
• 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

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