Molecular study and genotype–phenotype in Chinese female patients with 46, XY disorders of sex development

Abstract

Objective

The rare condition 46, XY disorders of sex development (DSDs) is characterized by the female phenotype and male karyotype. We aimed to describe the genetic basis of 46, XY DSDs in nine patients and the genotype–phenotype relationships of the genes involved.

Methods

Targeted next-generation sequencing (NGS) was used to analyze the underlying hereditary etiology in nine female patients with 46, XY DSDs. In silico analyses were used to predict the effects of novel variants on the protein function of the identified genes.

Results

Primary amenorrhea with the absence of puberty, inguinal hernia, and clitoridauxe were common complaints. All enrolled patients had a differential etiology by genetic testing, and five novel genetic variants involved in four genes (SRY, AR, NR5A1, and LHCGR) were identified. A novel nonsense variant of SRY c.51C > G was found in XY patients without testicles. Two novel heterozygous variants, i.e. c.265A > T (Ile89Leu) and c.422T > C (Val141Ala), of the LHCGR gene were found in male pseudo-hermaphroditism.

Conclusions

We expanded the genetic mutation spectrum and described in detail the genotype–phenotype relationships of 46, XY DSDs. DNA sequencing for SRY should be a priority in female patients with 46, XY DSDs. NGS is useful for clarifying genetic pathogenesis and could provide a basis for clinical diagnosis and treatments of patients with 46, XY DSDs.

46, XY性发育障碍的中国女性的分子研究和基因型表型 摘要

目的：罕见的46 XY性发育障碍（disorders of sex development, DSDs）以女性表型和男性核型为特征。我们旨在描述9例患者中46 XY DSDs的遗传基础以及相关基因的基因型-表型关系。

方法：靶向二代测序 (next-generation sequencing, NGS) 用于分析9名46 XY DSDs女性患者的潜在遗传病因。计算机分析用于预测新变异对已识别基因的蛋白质功能的影响。

结果：最常见的主诉是无青春期的原发性闭经、腹股沟疝和阴蒂肥大。通过基因测试, 所有入选患者都有不同的病因, 并确定了涉及四个基因（SRY、AR、NR5A1和LHCGR）的五种新的基因变体。在没有睾丸的XY患者中发现了一种新的SRY c.51C > G无义变体。在男性假两性畸形中发现了两种新的LHCGR基因杂合子变体, 即c.265A>T（Ile89Leu）和c.422T>c（Val141Ala）。

结论：我们扩展了基因突变谱, 并详细描述46 XY DSDs的基因型-表型关系。SRY 基因测序应该是46 XY DSDs 女性患者的优先选择。NGS有助于阐明遗传发病机制, 并可为46 XY DSDs患者的临床诊断和治疗提供依据。

Keywords:

• 46
• XY disorders of sex development
• novel gene variants
• genotype
• phenotype
• SRY

Acknowledgements

We thank the patients and their families for their participation in the study.

Author contributions

Study design and manuscript preparation: J.X.; data collection: Y.X. and C.C.; data analysis: Z.Z., J.W., and Z.B.; contribution of fund acquisition: X.K.

Disclosure statement

There is no conflict of interest declared.

Additional information

Funding

This work is supported by the National Key Research and Development Program of China supported by Ministry of Science and Technology [2018YFC1002203].