{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:30:37Z","timestamp":1790350237351,"version":"4.1.0"},"reference-count":39,"publisher":"The Endocrine Society","issue":"4","license":[{"start":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP25ek0109760"],"award-info":[{"award-number":["JP25ek0109760"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["25ek0109743"],"award-info":[{"award-number":["25ek0109743"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP25ek0109815"],"award-info":[{"award-number":["JP25ek0109815"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Congenital hypogonadotropic hypogonadism (CHH) is a genetically heterogeneous disorder, with multiple causative and candidate genes identified to date.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To clarify underlying genetic factors involved in the development of CHH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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 &amp;lt;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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgaf548","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T12:00:40Z","timestamp":1759406440000},"page":"1147-1158","source":"Crossref","is-referenced-by-count":2,"title":["Comprehensive Molecular Studies in 88 Japanese Patients 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