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

<p><b>Background: </b>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 <i>ANOS1</i> (<i>KAL1)</i>, <i>RNF216</i>,<i> WDR11</i>,<i> FGFR1</i>,<i> CHD7</i> and <i>POLR3A</i> genes is described, along with novel variants identified in patients with CHH by the present study.</p> <p><b>Methods:</b> Seven GnRH deficient unrelated Cypriot patients underwent whole exome sequencing (WES) by Next Generation Sequencing (NGS). The identified novel variants were initially examined by <i>in silico </i>computational algorithms and structural analysis of their predicted pathogenicity at the protein level was confirmed.</p> <p><b>Results:</b> In four nonrelated GnRH males, a novel X-linked pathogenic variant in <i>ANOS1 </i>gene, two novel autosomal dominant (AD) probably pathogenic variants in <i>WDR11 </i>and <i>FGFR1 </i>genes and one rare AD probably pathogenic variant in <i>CHD7</i> gene were identified. A rare autosomal recessive (AR) variant in the <i>SRA1</i> gene was identified in homozygosity in a female patient, whilst two other male patients were also respectively found to carry novel or previously reported rare pathogenic variants in more than one genes; <i>FGFR1</i>/<i>POLR3A </i>and <i>SRA1/RNF216</i>.</p> <p><b>Conclusion: </b>This report embraces the description of novel and previously reported rare pathogenic variants in a series of genes known to be implicated in the biological development of CHH. Notably, patients with CHH can harbor pathogenic rare variants in more than one gene which raises the hypothesis of locus-locus interactions providing evidence for digenic inheritance. The identification of such aberrations by NGS can be very informative for the management and future planning of these patients.</p>