<b><i>SLIT2</i></b> Rare Sequencing Variants Identified in Idiopathic Hypogonadotropic Hypogonadism
Jiayu Wu, Zhenghuan Fang, Xinying Wang, Zeng Wang, Yaguang Zhao, Fang Jiang, Danna Chen, Ruizhi Zheng, Jinchen Li, Meichao Men, Jia‐Da Li
Abstract
<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.