NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Clin Endocrinol (Oxf). 2021 Jul;95(1):153-162. doi: 10.1111/cen.14436. Epub 2021 Apr 30.
We aimed to analyse FGFR1 rare variants in a series of Chinese congenital hypogonadotropic hypogonadism (CHH) patients. In addition, we intended to understand the clinical characteristics and the response to treatment of CHH patients with FGFR1 rare variants.
A total of 357 CHH patients were recruited at Peking Union Medical College Hospital. We used Sanger sequencing to analyse FGFR1 gene. In silico analysis was carried out to study the pathogenicity of novel missense variants. The clinical, endocrinological and therapeutic effects from patients carrying FGFR1 rare variants were analysed retrospectively.
Thimissense mutations.rty patients in this series were found to harbour 29 FGFR1 rare variants, with 8 recurrent and 21 novel variants. After comprehensive analysis, 18 out of 21 novel variants were classified as likely pathogenic (LP) ones. These variants are widely spread throughout the FGFR1 gene and almost all FGFR1 functional domains, which exhibited no hot spot. Cryptorchidism, cleft palate and dental abnormality incidence in this CHH series that possessed FGFR1 LP variants were approximately 38.5%, 7.6% and 3.8%, respectively. Among patients who accepted the fertility-promoting treatment, 8 out of 10 patients succeeded in spermatogenesis.
Eighteen novel LP variants were found to expand the spectrum of FGFR1 rare variants. In CHH patients possessing FGFR1 variants, we found that the rate of spermatogenesis was high following fertility-promoting therapy and the existence of cryptorchidism may represent the underlying factors which affect spermatogenesis.
我们旨在分析一系列中国先天性低促性腺激素性性腺功能减退症（CHH）患者中的 FGFR1 稀有变异。此外，我们旨在了解携带 FGFR1 稀有变异的 CHH 患者的临床特征和对治疗的反应。
我们共招募了 357 名来自北京协和医院的 CHH 患者。我们使用 Sanger 测序分析 FGFR1 基因。进行了计算机分析以研究新错义变异的致病性。回顾性分析携带 FGFR1 稀有变异的患者的临床、内分泌和治疗效果。
在本系列中，有 29 种 FGFR1 稀有变异被发现存在于 3 种 THI 变异型患者中，其中 8 种为重复变异，21 种为新变异。经过综合分析，21 种新变异中有 18 种被归类为可能致病（LP）。这些变异广泛分布于 FGFR1 基因中，几乎涉及所有 FGFR1 功能域，不存在热点。在本 CHH 系列中，携带 FGFR1 LP 变异的患者中隐睾、腭裂和牙齿异常的发生率分别约为 38.5%、7.6%和 3.8%。在接受促生育治疗的患者中，有 10 名患者中的 8 名成功实现了精子发生。
发现了 18 种新的 LP 变异，扩展了 FGFR1 稀有变异的谱。在携带 FGFR1 变异的 CHH 患者中，我们发现促生育治疗后精子发生的比例较高，隐睾的存在可能是影响精子发生的潜在因素。
