Identification of gene variants in a cohort of hypogonadotropic hypogonadism: Diagnostic utility of custom NGS panel and WES in unravelling genetic complexity of the disease.

Congenital hypogonadotropic hypogonadism (CHH) is caused by dysfunction of hypothalamic gonadotropic-releasing hormone (GnRH) axis. The condition is both clinically and genetically heterogeneous with more than 40 genes implicated in pathogenesis. The goal of the present study was to identify causative mutations in CHH individuals employing 2 step procedure with a targeted NGS panel as first-line diagnostics and subsequently whole exome sequencing in unsolved cases. Known or novel potentially deleterious variants were found in 28 out of 47 tested CHH patients. Molecular diagnosis was reached in 19/47 CHH cases. In 13 cases monogenic variants were identified in ANOS1, FGFR1, GNRHR, CHD7, SOX10, and PROKR2, while 6 patients showed digenic or trigenic inheritance patterns. The achieved diagnostic rate was comparable to other studies on genetics of CHH. By evaluating and reporting more patients with CHH we make progress in unravelling its genetic complexity and move a step closer to personalised medicine.