Congenital hypogonadotropic hypogonadism (CHH) is caused by dysfunction of hypothalamic gonadotropic-releasing hormone (GnRH) axis. The condition is both clinically and genetically heterogeneous with more than 40 genes implicated in pathogenesis.

The goal of the present study was to identify causative mutations in CHH individuals employing 2 step procedure with a targeted NGS panel as first-line diagnostics and subsequently whole exome sequencing in unsolved cases.

Known or novel potentially deleterious variants were found in 28 out of 47 tested CHH patients. Molecular diagnosis was reached in 19/47 CHH cases. In 13 cases monogenic variants were identified in ANOS1, FGFR1, GNRHR, CHD7, SOX10, and PROKR2, while 6 patients showed digenic or trigenic inheritance patterns. The achieved diagnostic rate was comparable to other studies on genetics of CHH.

By evaluating and reporting more patients with CHH we make progress in unravelling its genetic complexity and move a step closer to personalised medicine.

先天性性腺功能减退性腺功能减退（CHH）是由下丘脑促性腺激素释放激素（GnRH）轴功能障碍引起的。该病在临床和遗传上都是异质的，与发病机理有关的基因超过40个。

本研究的目的是通过靶向NGS专家组的两步法鉴定CHH患者中的致病突变，作为一线诊断方法，随后在未解决的病例中进行整体外显子组测序。

在47位接受测试的CHH患者中，有28位发现了已知或新颖的潜在有害变体。在19/47 CHH病例中达到了分子诊断。在13例中，在ANOS1，FGFR1，GNRHR，CHD7，SOX10和PROKR2中鉴定出单基因变异，而6例患者表现出双基因或三基因遗传模式。达到的诊断率可与其他CHH遗传学研究相比。

通过评估和报告更多的CHH患者，我们在阐明其遗传复杂性方面取得了进展，并向个性化医学迈进了一步。