{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:53:30Z","timestamp":1793199210410,"version":"4.5.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","issue":"2","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:sec>\n<jats:title>Context<\/jats:title>\n<jats:p>Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Objective<\/jats:title>\n<jats:p>Genetic characterization of a large cohort of Brazilian CHH patients.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Design and patients<\/jats:title>\n<jats:p>A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes <jats:italic>ANOS1<\/jats:italic>, <jats:italic>FGFR1<\/jats:italic> and <jats:italic>GNRHR<\/jats:italic> were the most frequently affected. A novel homozygous splice site mutation was identified in the <jats:italic>GNRH1<\/jats:italic> gene and a deletion of the entire coding sequence was identified in <jats:italic>SOX10<\/jats:italic>. Deleterious variants in the <jats:italic>IGSF10<\/jats:italic> gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in <jats:italic>SPRY4<\/jats:italic>, <jats:italic>IL17RD<\/jats:italic>, <jats:italic>FGF17<\/jats:italic>, <jats:italic>IGSF1<\/jats:italic> and <jats:italic>FLRT3<\/jats:italic> genes.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.<\/jats:p>\n<\/jats:sec>","DOI":"10.1530\/eje-18-0764","type":"journal-article","created":{"date-parts":[[2019,6,14]],"date-time":"2019-06-14T15:28:58Z","timestamp":1560526138000},"page":"103-119","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":73,"title":["New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism"],"prefix":"10.1093","volume":"181","author":[{"given":"Lorena Guimaraes Lima","family":"Amato","sequence":"first","affiliation":[{"name":"1Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular\/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, S\u00e3o Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana Ribeiro","family":"Montenegro","sequence":"additional","affiliation":[{"name":"1Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular\/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, S\u00e3o Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio Marcondes","family":"Lerario","sequence":"additional","affiliation":[{"name":"1Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular\/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, S\u00e3o Paulo, Brasil"},{"name":"2Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander Augusto Lima","family":"Jorge","sequence":"additional","affiliation":[{"name":"3Unidade de Endocrinologia Genetica\/LIM25, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, S\u00e3o Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil","family":"Guerra Junior","sequence":"additional","affiliation":[{"name":"4Departamento de Pediatria, Faculdade de Ci\u00eancias M\u00e9dicas da Universidade Estadual de Campinas (UNICAMP), Campinas, S\u00e3o Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Schnoll","sequence":"additional","affiliation":[{"name":"1Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular\/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, S\u00e3o Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra Covallero","family":"Renck","sequence":"additional","affiliation":[{"name":"1Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular\/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, S\u00e3o Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ericka Barbosa","family":"Trarbach","sequence":"additional","affiliation":[{"name":"3Unidade de Endocrinologia Genetica\/LIM25, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, S\u00e3o Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine Maria Frade","family":"Costa","sequence":"additional","affiliation":[{"name":"1Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular\/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, S\u00e3o Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berenice Bilharinho","family":"Mendonca","sequence":"additional","affiliation":[{"name":"1Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular\/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, S\u00e3o Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Claudia","family":"Latronico","sequence":"additional","affiliation":[{"name":"1Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio 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