Point-of-care whole-exome sequencing of idiopathic male infertility
Point-of-care whole-exome sequencing of idiopathic male infertility
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DOI：
10.1038/gim.2018.10
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发表时间：
2018-11-01
影响因子：
8.8
通讯作者：
Crystal, Ronald G.
中科院分区：
文献类型：
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作者：
Fakhro, Khalid A.;Elbardisi, Haitham;Crystal, Ronald G.
目的：非梗阻性无精子症(NOA)影响1%的男性人群；然而，尽管有最先进的临床评估，对大多数患者来说，病因尚不清楚。方法：对8个有血缘关系的家系进行全外显子测序，将新发现的基因与已报道的基因相结合，建立NOA基因板，用于在75例无亲缘关系的特发性NOA受试者和74例生育对照中识别额外的变异。结果：在8个家系中的5个家系中，我们发现了CCDC155、NANOS2、SPO11、TEX14和WNK3与疾病分离的罕见有害隐性变异。这些基因是人类NOA的新基因，具有显著的睾丸特异性表达，小鼠功能证据支持它们在精子发生中的作用。在75名无关的NOA受试者中，我们确定了4名(类似于5.3%)在这些新发现的基因中存在额外的隐性变异，6名在先前报道的NOA基因中存在有害变异，总体遗传病因为13.3%的受试者与0例生育对照组(p=0.001)。结论：NOA影响数以百万计的男性，尽管进行了广泛的实验室评估，但其中许多人仍然是特发性的。这些患者中相当一部分(50%是家族性的，10%是散发性的)的遗传病因可能会在治疗时被WES发现。
Purpose: Nonobstructive azoospermia (NOA) affects 1% of the male population; however, despite state-of-the-art clinical assessment, for most patients the cause is unknown. We capitalized on an analysis of multiplex families in the Middle East to identify highly penetrant genetic causes.Methods: We used whole-exome sequencing (WES) in 8 consanguineous families and combined newly discovered genes with previously reported ones to create a NOA gene panel, which was used to identify additional variants in 75 unrelated idiopathic NOA subjects and 74 fertile controls.Results: In five of eight families, we identified rare deleterious recessive variants in CCDC155, NANOS2, SPO11, TEX14, and WNK3 segregating with disease. These genes, which are novel to human NOA, have remarkable testis-specific expression, and murine functional evidence supports roles for them in spermatogenesis. Among 75 unrelated NOA subjects, we identified 4 (similar to 5.3%) with additional recessive variants in these newly discovered genes and 6 with deleterious variants in previously reported NOA genes, yielding an overall genetic etiology for 13.3% subjects versus 0 fertile controls (p = 0.001).Conclusion: NOA affects millions of men, many of whom remain idiopathic despite extensive laboratory evaluation. The genetic etiology for a substantial fraction of these patients (> 50% familial and > 10% sporadic) may be discovered by WES at the point of care.