PDF(Pubmed)
Abstract：
UNASSIGNED: 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.
UNASSIGNED: A total of 67 patients with nIHH were enrolled in the study. NGS technology and a 38-gene panel were applied.
UNASSIGNED: 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 GNRHR (n = 5), TACR3 (n = 3), and CHD7, FGFR1, NSMF, BMP4, and NROB1 (n = 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 GNRHR: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.
UNASSIGNED: 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.
UNASSIGNED: A total of 67 patients with nIHH were enrolled in the study. NGS technology and a 38-gene panel were applied.
UNASSIGNED: 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 GNRHR (n = 5), TACR3 (n = 3), and CHD7, FGFR1, NSMF, BMP4, and NROB1 (n = 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 GNRHR: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.
UNASSIGNED: 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.
摘要：
■正常孤立性低促性腺激素性性腺功能减退症（nIHH）是一种临床和遗传异质性疾病。超过50个基因中的有害变异与IHH的病因有关，这也表明了双源性和寡源性的可能作用。控制GnRH神经元迁移/发育和下丘脑/垂体信号传导和发育的两类基因都与nIHH发病机理密切相关。本研究旨在探讨nIHH的遗传背景，进一步扩大nIHH基因型与表型的相关性。
■共有67例nIHH患者纳入研究。应用了NGS技术和38个基因组。
■在23例患者（34％）中发现了被视为至少一种致病性/可能致病性（P/LP）变异的病因缺陷。对于另外30个人，有证据表明有未知显著性变异(VUS)或良性变异(B)(45%).呈现P/LP改变的最常见的突变基因是GNRHR（n=5），TACR3（n=3），和CHD7，FGFR1，NSMF，BMP4和NROB1(各n=2)。在15％的受试者中观察到具有坚实临床意义（P/LP）的单基因变异，而19％的患者检测到寡基因缺陷。关于复发，对17例患者鉴定出影响10个基因的17个新的致病变异体。最反复的致病改变是GNRHR：p。Arg139His,在四个无关的受试者中检测到。另一个有趣的观察是，与下丘脑-垂体途径相关的基因比与GnRH相关的基因更容易发现P/LP缺陷。
■神经内分泌途径和相关基因的重要性日益增加，引起了对nIHH的越来越多的关注。然而,低估了VUS变异在IHH病因中的潜力，特别是那些出现复发的人，应该进一步阐明。
■共有67例nIHH患者纳入研究。应用了NGS技术和38个基因组。
■在23例患者（34％）中发现了被视为至少一种致病性/可能致病性（P/LP）变异的病因缺陷。对于另外30个人，有证据表明有未知显著性变异(VUS)或良性变异(B)(45%).呈现P/LP改变的最常见的突变基因是GNRHR（n=5），TACR3（n=3），和CHD7，FGFR1，NSMF，BMP4和NROB1(各n=2)。在15％的受试者中观察到具有坚实临床意义（P/LP）的单基因变异，而19％的患者检测到寡基因缺陷。关于复发，对17例患者鉴定出影响10个基因的17个新的致病变异体。最反复的致病改变是GNRHR：p。Arg139His,在四个无关的受试者中检测到。另一个有趣的观察是，与下丘脑-垂体途径相关的基因比与GnRH相关的基因更容易发现P/LP缺陷。
■神经内分泌途径和相关基因的重要性日益增加，引起了对nIHH的越来越多的关注。然而,低估了VUS变异在IHH病因中的潜力，特别是那些出现复发的人，应该进一步阐明。
