Lorena Guimaraes Lima Amato1, Luciana Ribeiro Montenegro1, Antonio Marcondes Lerario1,2, Alexander Augusto Lima Jorge3, Gil Guerra Junior4, Caroline Schnoll1, Alessandra Covallero Renck1, Ericka Barbosa Trarbach3, Elaine Maria Frade Costa1, Berenice Bilharinho Mendonca1, Ana Claudia Latronico1, Leticia Ferreira Gontijo Silveira1,5. 1. Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brasil. 2. Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. 3. Unidade de Endocrinologia Genetica/LIM25, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brasil. 4. Departamento de Pediatria, Faculdade de Ciências Médicas da Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brasil. 5. Departamento de Clínica Médica, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brasil.
Abstract
CONTEXT: 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. OBJECTIVE: Genetic characterization of a large cohort of Brazilian CHH patients. DESIGN AND PATIENTS: 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. RESULTS: Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 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 SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. CONCLUSIONS: 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.
CONTEXT: 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. OBJECTIVE: Genetic characterization of a large cohort of Brazilian CHH patients. DESIGN AND PATIENTS: 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. RESULTS: Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 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 SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. CONCLUSIONS: 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.
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