GnRH deficient patients with congenital hypogonadotropic hypogonadism: Novel genetic findings in ANOS1, RNF216, WDR11, FGFR1, CHD7 and POLR3A genes

Background: Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease caused by Gonadotropin-Releasing Hormone (GnRH) deficiency. So far a limited number of variants in several genes have been associated with the pathogenesis of the disease. In this original research and review manuscript the retrospective analysis of known variants in ANOS1 (KAL1), RNF216, WDR11, FGFR1, CHD7 and POLR3A genes is described, along with novel variants identified in patients with CHH by the present study.

Methods: Seven GnRH deficient unrelated Cypriot patients underwent whole exome sequencing (WES) by Next Generation Sequencing (NGS). The identified novel variants were initially examined by in silico computational algorithms and structural analysis of their predicted pathogenicity at the protein level was confirmed.

Results: In four nonrelated GnRH males, a novel X-linked pathogenic variant in ANOS1 gene, two novel autosomal dominant (AD) probably pathogenic variants in WDR11 and FGFR1...