Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011, China.
Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.
Asian J Androl. 2021 May-Jun;23(3):288-293. doi: 10.4103/aja.aja_65_20.
Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism (IHH) and an oligogenic etiology has been suggested. However, the associated genes may account for only approximately 50% cases. In addition, a genomic systematic pedigree analysis is still lacking. Here, we conducted whole exome sequencing (WES) on 18 unrelated men affected by IHH and their corresponding parents. Notably, one reported and 10 novel variants in eight known IHH causative genes (AXL, CCDC141, CHD7, DMXL2, FGFR1, PNPLA6, POLR3A, and PROKR2), nine variants in nine recently reported candidate genes (DCAF17, DCC, EGF, IGSF10, NOTCH1, PDE3A, RELN, SLIT2, and TRAPPC9), and four variants in four novel candidate genes for IHH (CCDC88C, CDON, GADL1, and SPRED3) were identified in 77.8% (14/18) of IHH cases. Among them, eight (8/18, 44.4%) cases carried more than one variant in IHH-related genes, supporting the oligogenic model. Interestingly, we found that those variants tended to be maternally inherited (maternal with n = 17 vs paternal with n = 7; P = 0.028). Our further retrospective investigation of published reports replicated the maternal bias (maternal with n = 46 vs paternal with n = 28; P = 0.024). Our study extended a variant spectrum for IHH and provided the first evidence that women are probably more tolerant to variants of IHH-related genes than men.
数十种基因与特发性低促性腺激素性性腺功能减退症（IHH）有关，并且已经提出了寡基因病因。然而，相关基因可能仅占大约 50%的病例。此外，仍然缺乏基因组系统谱系分析。在这里，我们对 18 名患有 IHH 的无血缘关系的男性及其相应的父母进行了全外显子组测序（WES）。值得注意的是，在 8 个已知的 IHH 致病基因（AXL、CCDC141、CHD7、DMXL2、FGFR1、PNPLA6、POLR3A 和 PROKR2）中报告了一个和 10 个新变体，在 9 个最近报道的候选基因（DCAF17、DCC、EGF、IGSF10、NOTCH1、PDE3A、RELN、SLIT2 和 TRAPPC9）中有 9 个变体，在 4 个新的 IHH 候选基因（CCDC88C、CDON、GADL1 和 SPRED3）中有 4 个变体，在 77.8%（14/18）的 IHH 病例中发现了变体。其中，8 例（8/18，44.4%）携带 IHH 相关基因的多个变体，支持寡基因模型。有趣的是，我们发现这些变体倾向于母系遗传（母亲携带 n = 17 与父亲携带 n = 7；P = 0.028）。我们对已发表报告的进一步回顾性调查复制了母系偏倚（母亲携带 n = 46 与父亲携带 n = 28；P = 0.024）。我们的研究扩展了 IHH 的变体谱，并提供了第一个证据，表明女性可能比男性对 IHH 相关基因的变体更耐受。
