New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

Author(s):Show less -

Lima Amato, Lorena Guimaraes ^[1] ; Montenegro, Luciana Ribeiro ^[1] ; Lerario, Antonio Marcondes ^{[2, 1]} ; Lima Jorge, Alexander Augusto ^[3] ; Guerra Junior, Gil ^[4] ; Schnoll, Caroline ^[1] ; Renck, Alessandra Covallero ^[1] ; Trarbach, Ericka Barbosa ^[3] ; Frade Costa, Elaine Maria ^[1] ; Mendonca, Berenice Bilharinho ^[1] ; Latronico, Ana Claudia ^[1] ; Gontijo Silveira, Leticia Ferreira ^{[1, 5]}

Affiliation

^[1] Univ Sao Paulo, Unidade Endocrinol Desenvolvimento, Lab Hormonios & Genet Mol LIM42, Disdplina Endocrinol & Metabol, Hosp Clin, Fac Med, Sao Paulo, SP - Brazil

^[2] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 - USA

^[3] Univ Sao Paulo, Unidade Endocrinol Genet LIM25, Disciplina Endocrinol & Metabol, Hosp Clin, Fac Med, Sao Paulo, SP - Brazil

^[4] Univ Estadual Campinas, UNICAMP, Fac Ciencias Med, Dept Pediat, Campinas, SP - Brazil

^[5] Univ Fed Minas Gerais, Fac Med, Dept Clin Med, Belo Horizonte, MG - Brazil

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF ENDOCRINOLOGY; v. 181, n. 2, p. 103-119, AUG 2019.
• Web of Science Citations: 2

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. (AU)

• FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support type: Research Projects - Thematic Grants