Objectives Hypogonadism is defined as inadequate sex hormone production due to defects in the hypothalamic-pituitary-gonadal axis. In recent years, rare single gene defects have been identified in both hypergonadotropic hypogonadism (Hh), and hypogonadotropic hypogonadism (HH) cases with no chromosomal anomalies. The aim of the present study is to investigate the underlying molecular genetic etiology and the genotype-phenotype relationship of a series of patients with Hh and HH. Methods In total, 27 HH and six Hh cases were evaluated. Clinical and laboratory features are extracted from patients’ hospital files. Whole exome sequencing (WES) analysis was performed. Results A total of 27 HH cases (15 female) (mean age: 15.8 ± 2.7 years) and six Hh patients (six females) (mean age: 14.9 ± 1.2 years) were included. In molecular genetic analysis, a pathogenic/likely pathogenic variant was identified in five (two patients from the same family) of 27 HH cases (two novel) and three of the six Hh. In HH group variants (pathogenic, likely pathogenic and variant of uncertain significance) were identified in KISS1R (n=2), PROK2 (n=1), FGFR1 (n=1), HS6ST1 (n=1), GNRH1 (n=1) genes. In the Hh group, splice-site mutations were detected in DCAF17 (n=1) and MCM9 (n=2) genes. Conclusions HH and Hh cases are genetically heterogeneous diseases due to oligogenic inheritance, incomplete penetrance, and variable expressivity. We found rare variants in CHH related genes in half of our HH cases, whereas they classified as pathogenic/likely pathogenic according to ACMG criteria in only about 15% of HH cases. Using advanced genetic analysis methods such as whole-genome sequencing and long-read sequencing may increase the mutation detection rate, which should always be associated with and expert genetic counseling to interpret the data.

中文翻译：

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特发性先天性性腺功能减退症队列的临床特征和分子遗传学分析

目的 性腺功能减退症被定义为由于下丘脑-垂体-性腺轴缺陷导致的性激素分泌不足。近年来，在没有染色体异常的高促性腺激素性性腺功能减退症 (Hh) 和促性腺激素性性腺功能减退症 (HH) 病例中都发现了罕见的单基因缺陷。本研究的目的是调查一系列 Hh 和 HH 患者的潜在分子遗传病因和基因型-表型关系。方法 共评估27例HH和6例Hh病例。从患者的医院文件中提取临床和实验室特征。进行全外显子组测序（WES）分析。结果共纳入27例HH患者（15名女性）（平均年龄：15.8±2.7岁）和6名HH患者（6名女性）（平均年龄：14.9±1.2岁）。在分子遗传分析中，在 27 个 HH 病例（两个新病例）中的 5 个（来自同一家族的两名患者）和 6 个 HH 中的三个中鉴定出致病性/可能致病性变异。在 HH 组中，在 KISS1R (n=2)、PROK2 (n=1)、FGFR1 (n=1)、HS6ST1 (n=1)、GNRH1 (n= 1）基因。在 Hh 组中，在 DCAF17 (n=1) 和 MCM9 (n=2) 基因中检测到剪接位点突变。结论 HH和Hh病例是由于寡基因遗传、不完全外显和可变表达导致的遗传异质性疾病。我们在一半的 HH 病例中发现了 CHH 相关基因中的罕见变异，而根据 ACMG 标准，它们仅在约 15% 的 HH 病例中归类为致病性/可能致病性。