Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland.
Department of Reproductive Health, Centre for Postgraduate Medical Education, Warsaw, Poland.
Front Endocrinol (Lausanne). 2024 Jul 1;15:1396805. doi: 10.3389/fendo.2024.1396805. eCollection 2024.
Normosmic isolated hypogonadotropic hypogonadism (nIHH) is a clinically and genetically heterogeneous disorder. Deleterious variants in over 50 genes have been implicated in the etiology of IHH, which also indicates a possible role of digenicity and oligogenicity. Both classes of genes controlling GnRH neuron migration/development and hypothalamic/pituitary signaling and development are strongly implicated in nIHH pathogenesis. The study aimed to investigate the genetic background of nIHH and further expand the genotype-phenotype correlation.
A total of 67 patients with nIHH were enrolled in the study. NGS technology and a 38-gene panel were applied.
Causative defects regarded as at least one pathogenic/likely pathogenic (P/LP) variant were found in 23 patients (34%). For another 30 individuals, variants of unknown significance (VUS) or benign (B) were evidenced (45%). The most frequently mutated genes presenting P/LP alterations were ( = 5) ( = 3), and , and ( = 2 each). Monogenic variants with solid clinical significance (P/LP) were observed in 15% of subjects, whereas oligogenic defects were detected in 19% of patients. Regarding recurrence, 17 novel pathogenic variants affecting 10 genes were identified for 17 patients. The most recurrent pathogenic change was :p.Arg139His, detected in four unrelated subjects. Another interesting observation is that P/LP defects were found more often in genes related to hypothalamic-pituitary pathways than those related to GnRH.
The growing importance of the neuroendocrine pathway and related genes is drawing increasing attention to nIHH. However, the underestimated potential of VUS variants in IHH etiology, particularly those presenting recurrence, should be further elucidated.
正常颅压孤立性促性腺激素低下症（nIHH）是一种临床表现和遗传学上具有异质性的疾病。超过 50 个基因的有害变异与 IHH 的病因有关，这也表明双基因性和寡基因性的可能性。控制 GnRH 神经元迁移/发育和下丘脑/垂体信号转导和发育的两类基因都强烈参与了 nIHH 的发病机制。本研究旨在探讨 nIHH 的遗传背景，并进一步扩展基因型-表型相关性。
共纳入 67 例 nIHH 患者进行研究。应用 NGS 技术和 38 基因panel。
23 例（34%）患者发现至少存在一个致病性/可能致病性（P/LP）变异。另外 30 例患者存在意义不明变异（VUS）或良性（B）变异（45%）。最常发生 P/LP 改变的突变基因是 （=5）（=3）， 和 ， 和 （=2 个）。在 15%的患者中观察到具有明确临床意义的单基因变异（P/LP），而在 19%的患者中检测到寡基因缺陷。关于复发，在 17 例患者中发现了 17 个影响 10 个基因的新的致病性变异。最常见的致病性改变是：p.Arg139His，在 4 个无血缘关系的患者中检测到。另一个有趣的观察是，与 GnRH 相关的基因相比，与下丘脑-垂体通路相关的基因中发现 P/LP 缺陷的频率更高。
神经内分泌途径和相关基因的重要性日益增加，引起了人们对 nIHH 的关注。然而，特别是那些具有复发倾向的 VUS 变异在 IHH 病因学中的潜在作用被低估了，需要进一步阐明。
