👤 Takahiro Ohyama

Congenital hypogonadotropic hypogonadism (CHH) is a genetically heterogeneous disorder, with multiple causative and candidate genes identified to date. To clarify underlying genetic factors involved in the development of CHH. 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 American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria and registered information in ClinVar. Twenty-seven pathogenic/likely pathogenic variants were identified in 30 patients through GPA performed for all 88 patients and in 4 patients through WES performed for 58 patients in whom no obvious disease-causing variants were revealed by GPA. They resided in previously known ANOS1 (6 variants in 7 patients), CHD7 (3 variants in 3 patients), FGFR1 (14 variants in 15 patients), PROKR2 (2 variants in 8 patients), and SOX10 (1 variant in 1 patient), and a hitherto unrecognized ZNF462 (1 variant in 1 patient). One patient had 2 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 individual was significantly larger in 54 CHH patients with no discernible pathogenic/likely pathogenic variants than in 100 control individuals. 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. Show less

The organ of Corti, the auditory organ of the inner ear, contains two types of sensory hair cells and at least seven types of supporting cells. Most of these supporting cell types rely on Notch-dependent expression of Hes/Hey transcription factors to maintain the supporting cell fate. Here, we show that Notch signaling is not necessary for the differentiation and maintenance of pillar cell fate, that pillar cells are distinguished by Hey2 expression, and that-unlike other Hes/Hey factors-Hey2 expression is Notch independent. Hey2 is activated by FGF and blocks hair cell differentiation, whereas mutation of Hey2 leaves pillar cells sensitive to the loss of Notch signaling and allows them to differentiate as hair cells. We speculate that co-option of FGF signaling to render Hey2 Notch independent also liberated pillar cells from the need for direct contact with surrounding hair cells, and enabled evolutionary remodeling of the complex cellular mosaic of the inner ear. Show less