New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism. Issue 2 (August 2019)

• Record Type: Journal Article
• Authors: Amato, Lorena Guimaraes Lima; Montenegro, Luciana Ribeiro; Lerario, Antonio Marcondes; Jorge, Alexander Augusto Lima; Guerra Junior, Gil; Schnoll, Caroline; Renck, Alessandra Covallero; Trarbach, Ericka Barbosa; Costa, Elaine Maria Frade; Mendonca, Berenice Bilharinho; Latronico, Ana Claudia; Silveira, Leticia Ferreira Gontijo
• Is Part Of: European journal of endocrinology. Volume 181:Issue 2(2019)
• Page Start: 103
• Page End: 119
• Publication Date: 2019-08
• Subjects: Endocrinology -- Periodicals; 616.4005
• DOI: 10.1530/EJE-18-0764
• Languages: English
• ISSNs: 0804-4643

Abstract

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.