Next-generation sequencing reveals genetic landscape in 46, XY disorders of sexual development patients with variable phenotypes
Next-generation sequencing reveals genetic landscape in 46, XY disorders of sexual development patients with variable phenotypes
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下一代测序揭示了 46 名具有可变表型的 XY 性发育障碍患者的遗传图谱
DOI：
10.1007/s00439-018-1879-y
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发表时间：
2018-03-01
期刊：
影响因子：
5.3
通讯作者：
Qiao, Jie
中科院分区：
文献类型：
--
作者：
Wang, Hao;Zhang, Lele;Qiao, Jie
性发育障碍（DSD）是罕见的先天性疾病，其中染色体，性腺或解剖性别是非典型的。目前，只有不到20%的患者得到了准确的基因诊断。对70 46，xy DSD患者进行了新一代靶向测序，包括33个候选基因和47个参与性别分化和发育的基因。功能分析评估了NR5A1 1个已报道的和9个新突变的表达和转录活性。总共在52例患者中发现了113个突变，其中包括40个基因中的86个新位点和27个已报道位点。其中，在46例XY型DSD患者中首次发现了来自19个基因的37个突变，包括EGF、LHX9和CST9。双等位基因突变9例，性染色体基因突变12例，NR5A1、BMP4、WT1单等位基因突变14例。在AR、SRD5A2和NR5A1中发现了更高频率的突变。研究表明，NR5A1的6个错义突变、1个移码突变和1个三核苷酸缺失突变会损害p.T29K和p.N44del变体的核聚集，从而损害其转激活能力。70例患者中有33例发现多重基因突变。靶向测序面板为46，xy DSD患者提供了一种有效的病因诊断方法，并扩大了候选基因和遗传模式。
Disorders of sexual development (DSD) are rare congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. Currently, less than 20% of patients receive an accurate genetic diagnosis. Targeted next-generation sequencing, consisting of 33 candidate genes and 47 genes involved in sexual differentiation and development, was performed on 70 46, XY DSD patients. Functional assays were performed to evaluate the expression and transcriptional activity of one reported and nine novel mutations of NR5A1. In total, 113 mutations, including 86 novel and 27 reported sites in 40 genes, were identified in 52 patients. Among them, 37 mutations from 19 genes were first identified in 46, XY DSD patients, including EGF, LHX9, and CST9. Nine patients displayed biallelic mutations, 12 had mutations in sex chromosome genes and 14 had monoallelic mutations in NR5A1, BMP4, and WT1. Higher frequency mutations were identified in AR, SRD5A2, and NR5A1. Six missense, one frameshift, and one three-nucleotide deletion mutations of NR5A1 were shown to impair the transactivation ability with an altered nuclear aggregation of p.T29K and p.N44del variants. Multiple genetic mutations were identified in 33 of the 70 patients. The targeted sequencing panel provides an efficient method for the etiological diagnosis of 46, XY DSD patients and expands the candidate genes and inherited patterns.