<b><i>SLIT2</i></b> Rare Sequencing Variants Identified in Idiopathic Hypogonadotropic Hypogonadism

<b><i>Introduction:</i></b> Idiopathic hypogonadotropic hypogonadism (IHH) is a rare reproductive disorder resulting from gonadotropin-releasing hormone (GnRH) deficiency. However, in only approximately half of patients with IHH is it possible to identify a likely molecular diagnosis. Mice lacking Slit2 have a reduced number or altered patterning of GnRH neurons in the brain. In order to assess the contribution of <i>SLIT2</i> to IHH, we carried out a candidate gene burden test analysis. <b><i>Methods:</i></b> A total of 196 IHH probands and 2,362 ethic-matched controls were recruited for this study. The IHH probands and controls were subjected to whole-exome sequencing. In the IHH patients with <i>SLIT2</i> variants and their available family members, detailed phenotyping and segregation analysis were performed. <b><i>Results:</i></b> Nine heterozygous <i>SLIT2</i> rare sequencing variants (RSVs) were identified in 13 probands, with a prevalence of 6.6%. Furthermore, we identified an increased mutational burden for <i>SLIT2</i> in this cohort (odds ratio = 2.2, <i>p</i> = 0.021). The segregation analysis of available IHH families revealed that the majority of <i>SLIT2</i> RSVs were inherited from unaffected or partially affected parents. <b><i>Conclusion:</i></b> Our study suggests <i>SLIT2</i> as a new IHH-associated gene and expands the clinical and genetic spectrum of IHH. Furthermore, <i>SLIT2</i> alone does not appear to be sufficient to cause the disorder, and it may interact with other IHH-associated genes to induce a clinical phenotype.