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SLIT2 rare sequencing variants identified in Idiopathic Hypogonadotropic Hypogonadism
Hormone Research in Paediatrics ( IF 2.6 ) Pub Date : 2022-07-07 , DOI: 10.1159/000525769
Jiayu Wu 1, 2, 3 , Zhenghuan Fang 4, 5, 6 , Xinying Wang 4, 5, 7 , Wang Zeng 4, 5, 7 , Yaguang Zhao 4, 5, 7 , Fang Jiang 4, 5, 7 , Dan-Na Chen 8 , Ruizhi Zheng 9 , Jinchen Li 4, 5, 6 , Meichao Men 10 , Jia-Da Li 4, 5, 7, 11
Affiliation  

Introduction: 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 SLIT2 to IHH, we carried out a candidate gene burden test analysis. Methods: A total of 196 IHH probands and 2362 ethic matched controls were recruited for this study. The IHH probands and controls were subjected to whole exome sequencing. In the IHH patients with SLIT2 variants and their available family members, detailed phenotyping and segregation analysis were performed. Results: Nine heterozygous SLIT2 rare sequencing variants (RSVs) were identified in 13 probands, with a prevalence of 6.6%. Furthermore, we identified an increased mutational burden for SLIT2 in this cohort (odds ratio = 2.2, p = 0.021). The segregation analysis of available IHH families revealed that the majority of SLIT2 RSVs were inherited from unaffected or partially affected parents. Conclusion: Our study suggests SLIT2 as a new IHH-associated gene and expands the clinical and genetic spectrum of IHH. Furthermore, SLIT2 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.


中文翻译:

在特发性低促性腺激素性腺功能减退症中发现的 SLIT2 罕见测序变异

简介:特发性低促性腺激素性腺功能减退症(IHH)是一种罕见的生殖系统疾病,由促性腺激素释放激素(GnRH)缺乏引起。然而,只有大约一半的 IHH 患者可以确定可能的分子诊断。缺乏 Slit2 的小鼠大脑中 GnRH 神经元的数量减少或模式改变。为了评估 SLIT2 对 IHH 的贡献,我们进行了候选基因负荷测试分析。方法:本研究共招募了 196 名 IHH 先证者和 2362 名伦理匹配对照。IHH 先证者和对照者接受了全外显子组测序。在具有 SLIT2 变体的 IHH 患者及其可用的家庭成员中,进行了详细的表型分析和分离分析。结果:在 13 名先证者中鉴定出 9 个杂合 SLIT2 罕见测序变异 (RSV),患病率为 6.6%。此外,我们发现该队列中 SLIT2 的突变负担增加(优势比 = 2.2,p = 0.021)。可用 IHH 家族的分离分析显示,大多数 SLIT2 RSV 遗传自未受影响或部分受影响的父母。结论:我们的研究表明 SLIT2 是一种新的 IHH 相关基因,并扩大了 IHH 的临床和遗传谱。此外,单独的 SLIT2 似乎不足以引起该疾病,它可能与其他 IHH 相关基因相互作用以诱导临床表型。可用 IHH 家族的分离分析显示,大多数 SLIT2 RSV 遗传自未受影响或部分受影响的父母。结论:我们的研究表明 SLIT2 是一种新的 IHH 相关基因,并扩大了 IHH 的临床和遗传谱。此外,单独的 SLIT2 似乎不足以引起该疾病,它可能与其他 IHH 相关基因相互作用以诱导临床表型。可用 IHH 家族的分离分析显示,大多数 SLIT2 RSV 遗传自未受影响或部分受影响的父母。结论:我们的研究表明 SLIT2 是一种新的 IHH 相关基因,并扩大了 IHH 的临床和遗传谱。此外,单独的 SLIT2 似乎不足以引起该疾病,它可能与其他 IHH 相关基因相互作用以诱导临床表型。
更新日期:2022-07-07
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