New insights from unbiased panel and whole-exome sequencing in a large Chinese cohort with disorders of sex development
New insights from unbiased panel and whole-exome sequencing in a large Chinese cohort with disorders of sex development
复制标题
来自中国性发育障碍大型队列的无偏面板和全外显子组测序的新见解。
DOI：
10.1530/eje-19-0111
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发表时间：
2019-09-01
影响因子：
5.8
通讯作者：
Wang, Jian
中科院分区：
文献类型：
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作者：
Xu, Yufei;Wang, Yirou;Wang, Jian
背景：非染色体型性发育障碍 (DSD) 的诊断长期以来一直具有挑战性。目前还没有对大型中国 DSD 队列进行概述的研究。 目的：通过无偏倚的大规模组测序和全外显子组测序（WES）在大型中国 DSD 队列中确定病因诊断。 设计：根据 DSD 纳入标准招募患者。所应用的panel包含2742个已知的致病基因，包括所有已知的DSD诊断基因。方法：进行了靶向panel测序（TPS），并对识别出的候选变异进行了验证。根据既定指南评估变异致病性。对随机选择的阴性样本进行 WES。结果：本研究纳入了 125 名患者。 TPS 鉴定出 75 个变异，其中 31 个变异为首次报告。致病变异和可能致病变异分别占38.7%和30.7%。根据临床确定性，46,XY 和 46,XX DSD 患者的病因诊断率分别为 46.9% 和 10.3%。我们报告了新的候选基因（BMPR1B、GNAS、GHR）和超出预期 DSD 基因型-表型相关性的拷贝数变异区域，并确定了 5 α 还原酶缺乏症患者的创始人突变（SRDSA2 p.R227Q）。在随机选择的阴性样本中进一步进行 WES，仅在 14 个阴性样本中识别出一个不确定意义的变异，表明 WES 并没有提高诊断率。结论：这是在中国 46,XY 和 46,XX DSD 患者大型队列中应用无偏 TPS 的第一份报告。我们的研究结果扩大了中国人群中罕见类型 DSD 的基因、突变和表型谱，并为当前对 DSD 病因的理解提供了新的见解。
Context: Diagnosis of non-chromosomal type disorders of sex development (DSD) has long been challenging. There is still no research on overview of a large Chinese DSD cohort.Objective: To determine the etiologic diagnosis through unbiased large-scale panel sequencing and whole-exome sequencing (WES) within a large Chinese DSD cohort.Design: Patients were recruited according to the inclusion criteria of DSD. The applied panel contains 2742 known disease-causing genes, including all known diagnostic genes for DSD.Methods: Targeted panel sequencing (TPS) was performed, and identified candidate variants were verified. Variant pathogenicities were evaluated according to established guidelines. WES was performed for randomly selected negative samples.Results: This study included 125 patients. Seventy-five variants were identified by TPS and 31 variants were reported for the first time. Pathogenic and likely pathogenic variants accounted for 38.7 and 30.7%, respectively. On the basis of clinical certainty, etiologic diagnostic rates of 46.9 and 10.3% were obtained for 46,XY and 46,XX DSD patients, respectively. We reported novel candidate genes (BMPR1B, GNAS, GHR) and regions of copy number variants outside the expected DSD genotype-phenotype correlation and determined a founder mutation (SRDSA2 p.R227Q) in patients with 5 alpha-reductase deficiency. Further WES in randomly selected negative samples identified only one among 14 negative samples as a variant of uncertain significance, indicating that WES did not improve the diagnostic rate.Conclusions: This is the first report of the applying unbiased TPS in a large Chinese cohort of patients with 46,XY and 46,XX DSD. Our findings expand the gene, mutation and phenotype spectra of the rare types of DSD in the Chinese population and provide new insight into the current understanding of the etiologies of DSD.