New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

Lorena Guimaraes Lima Amato,Leticia Ferreira Gontijo Silveira,Berenice Bilharinho Mendonca,Alexander Augusto Lima Jorge,Alessandra Covallero Renck,Ericka Barbosa Trarbach,Caroline Schnoll,Gil Guerra Junior,Elaine Maria Frade Costa,Luciana Ribeiro Montenegro,Antonio Marcondes Lerario,Ana Claudia Latronico

doi:10.1530/eje-18-0764

Abstract

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. Genetic characterization of a large cohort of Brazilian CHH 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. 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. 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.

Highlights

Normal pubertal development is dependent on the secretion and proper action of the gonadotropin-releasing hormone (GnRH), produced by a small number of neurons located in the ventromedial hypothalamus (1, 2)
Because of the common embryonic origin of olfactory and GnRH neurons, Congenital hypogonadotropic hypogonadism (CHH) is often associated with olfactory defects, characterizing Kallmann syndrome (KS), which corresponds to approximately 50–60% of CHH cases (3)
Some of these genes have been classically known to cause CHH, such as ANOS1, which is associated with the X-linked form of KS, with a severe reproductive phenotype, whereas GNRHR mutations are a common cause of autosomal recessive normosmic CHH (3, 6, 7, 8, 9, 10)

Summary

Introduction

Normal pubertal development is dependent on the secretion and proper action of the gonadotropin-releasing hormone (GnRH), produced by a small number of neurons located in the ventromedial hypothalamus (1, 2). A growing list of genes has been implicated in the molecular pathogenesis of CHH These genes are involved in different stages of the regulation of GnRH production, secretion or action, as well as in the process of embryonic neuronal migration (3, 4, 5). Some of these genes have been classically known to cause CHH, such as ANOS1 (previously termed KAL1), which is associated with the X-linked form of KS, with a severe reproductive phenotype, whereas GNRHR mutations are a common cause of autosomal recessive normosmic CHH (nCHH) (3, 6, 7, 8, 9, 10). Despite the vast history of the genetic causes of CHH, until recently only about 30% of these patients had a recognized molecular diagnosis (4)

Objectives

Methods

Results

Conclusion