CHD7 – Hypogonadotropic Hypogonadism

CHD7 haploinsufficiency is increasingly recognized as a cause of idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome, phenotypes characterized by delayed puberty, low gonadotropins, and anosmia. Clinical validity is supported by approximately 48 unrelated probands with heterozygous CHD7 variants identified in IHH/KS cohorts, including seven sporadic mutations in 197 patients (PMID:18834967) and 41 probands in a 783-patient IGD screen (PMID:25472840). Functional concordance with human phenotypes has been demonstrated through zebrafish otolith assays and in vitro nucleosome remodeling studies. These data fulfill criteria for a Strong gene–disease association.

1 Assess Clinical Validity

• ClinGen category: Strong
• Rationale: 48 probands across independent cohorts, absence of variants in controls, and functional assays consistent with pathogenicity.

2 Genetic Evidence

• Inheritance: Autosomal dominant (heterozygous variants).
• Segregation: No large pedigrees; most cases are sporadic de novo or private variants.
• Case series: Seven heterozygous CHD7 mutations in 197 IHH/KS patients (PMID:18834967); 41 rare sequence variants in 783 IGD patients (5.2%) (PMID:25472840).
• Variant spectrum: Missense and splice-site variants; example: c.2819C>T (p.Pro940Leu).

3 Functional / Experimental Evidence

• Mechanism: Haploinsufficiency leading to impaired ATP-dependent chromatin remodeling.
• Assays: Patient mutations reduce CHD7 remodeling activity in vitro (PMID:23134727); IGD-associated alleles show loss of function in zebrafish otolith models (PMID:25472840).

4 Addressing Conflicting Evidence

A large population study found no association between common HH-gene variants and age at menarche in 1801 women (PMID:18728166), suggesting that CHD7 pathogenicity is limited to rare deleterious alleles.

5 Integration & Conclusion

Heterozygous CHD7 variants cause a spectrum from syndromic CHARGE to isolated IHH/KS by disrupting chromatin remodeling required for GnRH neuron development. Genetic findings are reinforced by convergent functional data, supporting CHD7 testing in patients with delayed puberty and anosmia.

Key Take-home: CHD7 is a clinically actionable gene for dominant hypogonadotropic hypogonadism, guiding molecular diagnosis and management.

References

• American journal of human genetics • 2008 • Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome PMID:18834967
• 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
• The Journal of Clinical Endocrinology and Metabolism • 2008 • Association studies of common variants in 10 hypogonadotropic hypogonadism genes with age at menarche PMID:18728166

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