A novel GNRHR gene mutation causing Congenital Hypogonadotropic Hypogonadism (CHH) in a Brazilian Kindred

Abstract

Congenital Hypogonadotropic Hypogonadism (CHH) is a challenging inherited endocrine disorder characterized by absent or incomplete pubertal development and infertility due to low action/secretion of the hypothalamic gonadotrophin‐releasing hormone (GnRH). Given a growing list of gene mutations accounting for CHH, application of massively parallel sequencing has become an excellent molecular diagnosis approach since it has enabled simultaneous evaluation of many genes. The study proposes the use of Whole Exome Sequencing (WES) to identify causative and modifying mutations based on a phenotype‐genotype CHH analysis by in‐house exome pipeline. Based on 44 known genes related to CHH in humans, we were able to identify a novel homozygous GNRHR p.Thr269Met mutant, which segregates with CHH kindred and was predicted to be deleterious by in silico analysis. A functional study measuring intracellular inositol phosphate (IP) when stimulated with GnRH on COS‐7 cells confirmed that the p.Thr269Met GnRHR mutant performed greatly diminished IP accumulation relative to the transfected wild‐type GnRHR. Additionally, the proband carries three heterozygous variants in CCDC141 and one homozygous in SEMA3A gene, but their effects in modifying the phenotype are uncertain. Since they do not segregate with reproductive phenotype in family members, we advocate they do not contribute to CHH oligogenicity. WES proved to be useful for CHH molecular diagnosis and reinforced its benefit for identifying heterogeneous genetic disorders. Our findings expand the GnRHR mutation spectrum and phenotype‐genotype correlation in CHH.

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