New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

Abstract

Context: Congenital hypogonadotropic hypogonadism (CHH) is a rare condi tion caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but mo st 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 pa tients. 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 iden tified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice si te mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identifie d 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 identifi ed in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. Conclusions: This is a large study of the molecular genetics of CHH providi ng 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 clinica l genetic testing in the future.