Zhang Ning, You Shuoming, Guo Jingjing, Chang Xingyu, Qiu Junjun, Hua Keqin
Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China.
Front Endocrinol (Lausanne). 2025 Apr 11;16:1560698. doi: 10.3389/fendo.2025.1560698. eCollection 2025.
More than 60% of cases of 46,XY gonadal dysgenesis (GD), a condition classified as a disorder of sex development (DSD), remain unexplained, which is due to high genetic and clinical heterogeneity. Whole-exome sequencing (WES) is an efficient primary genetic diagnostic method; specifically, the use of WES in patients with 46,XY GD to explore the underlying genetic variants of the disorder may help us gain a deeper understanding of the pathogenesis and phenotype-genotype correlation of 46,XY GD.
We performed WES and pedigree studies to investigate the underlying genetic etiology of patients with 46,XY GD (six patients and six familial controls). The variants were confirmed via Sanger sequencing, and detailed functional prediction of the discovered genetic variants was conducted. Furthermore, we performed protein structural analysis and protein thermodynamic analysis to further explore the pathogenicity of these variants. variants in patients with 46,XY GD with/without CHD and patients with cardiac disease alone were also analyzed.
We identified three novel pathogenic variants in :c.725G>C(p.Cys242Ser), :c.370_380del(p.Pro124Glyfs*21), and :c.2020C>T(p.Arg674Trp), as well as one previously reported :c.1016G>A(p.Arg339Gln) variant. These variant sites are conserved among species and were predicted to be damaging according to functional algorithms and protein analyses. Additionally, 71.4% of the GATA4 amino acid changes in 46,XY GD were located in or close to the N-terminal zinc finger (N-ZF) domain. However, most pathogenic variants (31.82%) in patients with isolated cardiac diseases were located in transactivation domain 1 (TAD1), and only 9.09% of the variants were located in the N-ZF domain.
The N-ZF domain may play an exclusive role in the mechanism of GATA4 in the pathogenesis of 46,XY GD; therefore, this domain may be an interesting topic for future investigation. This study enhances our understanding of the genetic etiology and pathogenesis of 46,XY GD, which may aid in the diagnosis and intervention of this disorder.
46,XY性腺发育不全（GD）是一种性发育障碍（DSD），超过60%的病例病因不明，这是由于其高度的遗传和临床异质性。全外显子测序（WES）是一种有效的原发性基因诊断方法；具体而言，对46,XY GD患者使用WES来探索该疾病潜在的基因变异，可能有助于我们更深入地了解46,XY GD的发病机制及表型-基因型相关性。
我们对46,XY GD患者（6例患者和6个家族对照）进行了WES和家系研究。通过桑格测序确认变异，并对发现的基因变异进行详细的功能预测。此外，我们进行了蛋白质结构分析和蛋白质热力学分析，以进一步探究这些变异的致病性。还分析了有/无先天性心脏病（CHD）的46,XY GD患者以及单独患有心脏病患者的变异情况。
我们在[具体基因名称未给出]中鉴定出三个新的致病变异：c.725G>C（p.Cys242Ser）、c.370_380del（p.Pro124Glyfs*21）和c.2020C>T（p.Arg674Trp），以及一个先前报道的c.1016G>A（p.Arg339Gln）变异。这些变异位点在物种间保守，根据功能算法和蛋白质分析预测具有损害性。此外，46,XY GD中71.4%的GATA4氨基酸变化位于或靠近N端锌指（N-ZF）结构域。然而，孤立性心脏病患者中大多数致病变异（31.82%）位于反式激活结构域1（TAD1），只有9.09%的变异位于N-ZF结构域。
N-ZF结构域可能在GATA4参与46,XY GD发病机制中发挥独特作用；因此，该结构域可能是未来研究的一个有趣课题。本研究增进了我们对46,XY GD遗传病因和发病机制的理解，这可能有助于该疾病的诊断和干预。
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