一个携带相同 AR 基因变异的中国家族中雄激素不敏感综合征患者的不同表型和生育结果。

IF 2.1 4区 医学 Q3 GENETICS & HEREDITY
Hao Geng, Dongdong Tang, Kuokuo Li, Chuan Xu, Chao Wang, Xiansheng Zhang, Xiaojin He, Yunxia Cao
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引用次数: 0

摘要

背景:雄激素不敏感综合征(AIS)是一种罕见的遗传性疾病,主要是由于雄激素受体(AR)基因突变导致的雄激素抵抗。它可表现为完全性 AIS、部分性 AIS 和轻度 AIS。虽然已有研究将特定的 AR 基因突变与 AIS 表型联系起来,但也有报道称,具有相同 AR 基因突变的患者会出现不同的临床 AIS 表型。迄今为止,人们对表型与基因型之间的确切相关性仍不甚了解:我们对来自一个中国家庭的四名不同类型的 AIS 患者进行了深入调查。临床表现、实验室检查和生育结果均有详细记录。此外,我们还进行了基因测序,以检测可能的致病变异:结果:全外显子组测序在所有四名患者中发现了AR基因的半杂合错义变异(c.2263T > C; p.Phe755Leu),这些患者均有不同程度的少精症和异质性精子发生。被诊断为部分无精子症的原告因患有非梗阻性无精子症而选择用捐献的精子进行治疗,而被诊断为完全无精子症的哥哥姐姐则被当作女孩抚养。他的两个舅舅都被诊断为轻度AIS,大舅自然生育了两个女孩,而小舅则因为严重少精子症而利用辅助生殖技术怀上了一个男孩:我们的研究首次在四名受影响的患者中发现了相同的AR变体(c.2263T > C;p.Phe755Leu),这四名患者的AIS表型和生育结果差异很大,从而大大扩展了AIS的表型谱。值得注意的是,我们清楚地揭示了具有相同 AR(c.2263T > C;p.Phe755Leu)变异的 AIS 患者的不同生育结果,这为携带该变异的男性可能通过自然或结合辅助生殖技术获得生物学后代提供了可靠的证据。此外,我们的研究还强调了雄激素浓度在形成AIS表型多样性方面的潜在作用,值得进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Diverse phenotypes and fertility outcomes of patients with androgen insensitivity syndrome in a Chinese family harboring identical AR gene variant.

Background: Androgen insensitivity syndrome (AIS) is a rare genetic disorder characterized by resistance to androgens, mainly due to mutations in the androgen receptor (AR) gene. It can manifest as complete AIS, partial AIS and mild AIS. While there have been studies linking specific AR gene mutations to AIS phenotypes, different clinical AIS phenotypes are also reported in patients with the same AR gene mutation. So far, the precise correlations between phenotypes and genotypes remain incompletely understood.

Methods: We conducted a thorough investigation involving four patients diagnosed with different types of AIS from a single Chinese family. Clinical manifestations, laboratory examinations, and fertility outcomes were well-documented. Furthermore, we performed genetic sequencing to detect possible pathogenetic variants.

Results: Whole exome sequencing identified a hemizygous missense variant (c.2263T > C; p.Phe755Leu) of AR gene in all four affected patients with different degrees of undermasculinisation and heterogeneous spermatogenesis. The proband, diagnosed with partial AIS, opted for treatment with donated sperm due to non-obstructive azoospermia, while their older sibling, diagnosed with complete AIS, was raised as a girl. His two maternal uncles were both diagnosed with mild AIS, the older uncle fathered two girls naturally, whereas the younger uncle utilized assisted reproductive technology to conceive a boy because of severe oligoasthenozoospermia.

Conclusion: Our study first identified the same AR variant (c.2263T > C;p.Phe755Leu) in four affected patients displaying highly diverse phenotypes of AIS and fertility outcomes, thereby significantly expanding the phenotypic spectrum of AIS. Notably, we presented a clear insight into different fertility outcomes of AIS patients with identical AR (c.2263T > C;p.Phe755Leu) variant, which provided reliable evidence that males harboring this variant may obtain biological offspring naturally or in combination with assisted reproductive technology. Furthermore, our study underscored the potential role of androgen concentration in shaping the phenotypic diversity of AIS, warranting further investigation.

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来源期刊
BMC Medical Genomics
BMC Medical Genomics 医学-遗传学
CiteScore
3.90
自引率
0.00%
发文量
243
审稿时长
3.5 months
期刊介绍: BMC Medical Genomics is an open access journal publishing original peer-reviewed research articles in all aspects of functional genomics, genome structure, genome-scale population genetics, epigenomics, proteomics, systems analysis, and pharmacogenomics in relation to human health and disease.
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