A novel GNRHR gene mutation causing congenital hypogonadotrophic hypogonadism in a Brazilian kindred

• DOI: 10.1111/jne.12658
• Publication Date: 2018-11-11T09:04:44Z
• Authors: Silvia Regina Cor...; Jessica da Silva ...; Marina Malta Letr...; Rafael Filipelli; David Santos Marc...; Andre Yuji Oku; Gilberto Koiti Fu...; Eugenia Verônica ...; Flavia Amanda Cos...; Miguel Mitne‐Neto; Magnus R. Dias‐da...
• Keywords: Hypogonadotrophic hypogonadism; GNRHR; Proband; Exome; Compound heterozygosity

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