Comprehensive Molecular Studies in 88 Japanese Patients With Congenital Hypogonadotropic Hypogonadism.

Background: Congenital hypogonadotropic hypogonadism (CHH) is a genetically heterogeneous disorder, with multiple causative and candidate genes identified to date.

Methods: We examined 88 Japanese patients with CHH using gene panel analysis (GPA) for 14 representative causative genes and whole exome sequencing (WES) which was initially focused on 41 causative/candidate genes and subsequently expanded to other genes. We extracted rare variants (frequency of <0.01) and performed pathogenic assessment using refined ACMG/AMP criteria and registered information in ClinVar.

Results: Twenty-seven pathogenic/likely pathogenic variants were identified in 30 patients through GPA performed for all the 88 patients and in four patients through WES performed for 58 patients in whom no obvious disease-causing variants were revealed by GPA. They resided in previously known ANOS1 (six variants in seven patients), CHD7 (three variants in three patients), FGFR1 (14 variants in 15 patients), PROKR2 (two variants in eight patients), and SOX10 (one variant in one patient), and hitherto unrecognized ZNF462 (one variant in one patient). One patient had two variants. Additionally, potentially CHH-related variants were detected in 12 genes including SEMA4D and CDH2 postulated on the CHH-related molecular network. Furthermore, in the 41 CHH-related genes, the frequency of oligogenicity was significantly higher and the number of rare variants per subject was significantly larger in 54 CHH patients with no discernible pathogenic/likely pathogenic variants than in 100 control subjects.

Conclusion: The results support the notion that CHH occurs not only as a monogenic disorder but also as an oligogenic/multifactorial disorder, and suggest the involvement of ZNF462, SEMA4D, and CDH2 variants in the development of CHH.