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北京大学学报（医学版） ›› 2026, Vol. 58 ›› Issue (2): 327-331. doi: 10.19723/j.issn.1671-167X.2026.02.016

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17例女性特发性低促性腺激素性腺功能减退症患者遗传变异分析

陈琪琪1, 王海宁2, 刘烨2, 智旭1,*()   

  1. 1. 北京大学第三医院妇产科，生殖医学中心；女性生育力促进全国重点实验室；国家妇产疾病临床医学研究中心(北京大学第三医院)；辅助生殖教育部重点实验室(北京大学)；生殖内分泌与辅助生殖技术北京市重点实验室，北京 100191
    2. 北京大学第三医院内分泌科，北京 100191
  • 收稿日期:2024-03-16 出版日期:2026-04-18 发布日期:2026-03-12
  • 通讯作者: 智旭
  • 基金资助:
    国家重点研发计划专项(2022YFC2703902); 国家自然科学基金(82370896); 首都卫生发展科研专项(2022-2-4095)

Genetic variants analysis of 17 female patients with idiopathic hypogonadotropic hypogonadism

Qiqi CHEN1, Haining WANG2, Ye LIU2, Xu ZHI1,*()   

  1. 1. Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Peking University Third Hospital; State Key Laboratory of Female Fertility Promotion; National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital); Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China
    2. Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
  • Received:2024-03-16 Online:2026-04-18 Published:2026-03-12
  • Contact: Xu ZHI
  • Supported by:
    the National Key Research and Development Program of China(2022YFC2703902); National Natural Science Foundation of China(82370896); Capital Health Development Research Special Project(2022-2-4095)

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摘要：

目的: 分析女性特发性低促性腺激素性腺功能减退症(idiopathic hypogonadotropic hypogonadism, IHH)患者的临床表型特点及遗传学检测资料, 探究其遗传学病因及遗传模式。方法: 招募21例女性IHH患者, 依据是否存在嗅觉异常分为非嗅觉异常IHH组及卡尔曼综合征(Kallmann syndrome, KS)组, 收集并分析其临床资料。通过全外显子组测序及Sanger测序分析遗传学病因, 包括已知疾病致病基因相关变异位点。针对PLXNA1错义变异使用Alphafold2进行突变体蛋白质结构预测。结果: 非嗅觉异常IHH组和KS组基线资料差异无统计学意义。21例患者中有17例患者及其家系成员进行外周血采集及测序, 其中4例检出明确致病性基因变异, 涉及FGFR1、PROKR2基因, 检出率为23.5%, 其余13例患者未获得明确遗传诊断。2例KS患者未检出已知致病性基因变异, 均杂合携带PLXNA1: c.3401G>A变异, 该错义变异导致1134氨基酸位点疏水性改变, 但不携带丛状蛋白通路其他基因变异位点。4例患者存在相关家族史, 检出携带IHH相关风险基因变异, 涉及FGFR1、CHD7、POLR3B基因。由于位点致病性评级仅为临床意义不明, 且不符合基因型-表型家系共分离, 所以部分患者未能明确遗传诊断。临床治疗方案主要包括应用激素替代药物维持第二性征及人工月经周期, 并使用促性腺激素进行促排卵治疗以获得生育力。结论: 女性IHH患者遗传学病因复杂且存在多基因致病遗传模式, 遗传家系患者及散发患者存在一定遗传风险; PLXNA1: c.3401G>A变异位点可能为KS风险变异位点。

关键词: 性腺功能减退症, 卡尔曼综合征, 全外显子组测序, PLXNA1

Abstract:

Objective: To analyze the clinical phenotype characteristics and genetic testing data of idiopathic hypogonadotropic hypogonadism (IHH) female patients, aiming to improve the understanding of genetic etiology and inheritance patterns among female patients. Methods: This study recruited twenty-one female patients and their clinical data were collected and analyzed. Based on the olfaction function, the patients were divided into normosmic IHH group and Kallmann syndrome (KS) group. Whole exome sequencing and Sanger sequencing were performed to screen for underlying genetic etiology including genetic variants of known pathogenic genes and PLEXIN pathway genes. Alphafold2 was used for mutant protein structure prediction of PLXNA1 missense mutation. Results: Normosmic IHH patients and KS patients had no difference in baseline clinical data. Among the 21 recruited patients, 17 patients and their immediate family members' peripheral blood was collected for sequencing, and four patients were found carrying pathogenic variants involving FGFR1 and PROKR2, and the pathogenic variant carrying rate was 23.5%. The remaining 13 patients didn't obtain a specific genetic diagnosis. Two KS patients withoutknown pathogenic variants carried the same heterozygous variant PLXNA1: c.3401G>A but no other PLEXIN pathway gene variants. The missense mutation caused hydrophobicity change of the 1134 amino acid loci of PLXNA1. Four patients with family history carried relevant gene variants involving FGFR1, CHD7 and POLR3B. However, the genetic diagnosis of some patients wasn't reached because the pathogenicity of these variants only reached variants of unknown significance based on American College of Medical Genetics and Genomics (ACMG) guidelines and the genotype-phenotype co-segregation within family was inconsistent. Female IHH patients could only maintain secondary sex characteristics and artificial menstruation through hormone replacement treatment and gain fertility by gonadotropin ovulation sti-mulating therapy. Conclusion: Female IHH patients have complex genetic etiology and polygenic inheri-tance mode. Both hereditary and sporadic patients may have various degrees of genetic inheritance risk. The missense variant PLXNA1: c.3401G>A might be a potential risk variant of KS.

Key words: Hypogonadism, Kallmann syndrome, Whole exome sequencing, PLXNA1

中图分类号: 

  • R394.8

表1

21例女性IHH患者临床资料"

Items nIHH (n=15) KS (n=6) Statistics P
Age/years 31.0 (25.0, 33.0) 27.0 (22.5, 33.3) Z=-0.981 0.326
BMI/(kg/m2) 21.43 (19.93, 22.48) 23.84 (21.77, 25.38) Z=-1.815 0.070
FSH/(IU/L) 0.55 (0.25, 1.87) 0.75 (0.22, 2.57) Z=-0.078 0.938
LH/(IU/L) 0.23 (0.11, 0.73) 0.41 (0.10, 0.71) Z=-0.078 0.938
E2/(ng/L) 12.00 (10.00, 26.40) 14.80 (9.98, 21.98) Z=-0.397 0.692
P/(μg/L) 0.70 (0.11, 0.87) 0.83 (0.35, 1.83) Z=-1.092 0.275
PRL/(μg/L) 10.05±18.86 18.88±25.92 t=-0.872 0.394
T/(ng/dL) < 0.69 < 0.69

图1

PLXNA1变异位点Sanger测序验证"

图2

PLXNA1变异蛋白质结构预测"

图3

4例IHH女性患者遗传家系图"

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