Causal Genetic Variants in Stillbirth. Reply.
Causal Genetic Variants in Stillbirth. Reply.
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死产的因果遗传变异。
DOI：
10.1056/nejmc2032136
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Goldstein,DavidB
中科院分区：
文献类型：
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作者：
Stanley,KateE;Wapner,RonaldJ;Goldstein,DavidB
背景在大多数情况下，死产的原因仍然不明，尽管详细的临床和实验室评估。大约10%到20%的死产归因于染色体异常。然而，单核苷酸变异和小的插入和缺失exomes.MethodsWe产生的外显子组测序数据为246死产的情况下，并遵循既定的指导方针，以确定致病变异的疾病相关基因的因果性质已经understudied。这些基因包括那些与死产相关的基因和强候选基因。我们还评估了18,653个基因的贡献，在病例对照分析分层的功能变异（这里描述为“不容忍”的变化）的程度耗尽。ResultsWe确定了15的246例死产（6.1%）涉及7个基因，已牵连在死产和6个疾病基因，是很好的候选人表型扩张的分子诊断。在我们评估的病例中，我们还发现在人群中不耐受这种变异的基因中富集了功能丧失变异（比值比，2.15; 95%置信区间[CI]，1.46至3.06）。不耐受基因中的功能丧失变异集中在与人类疾病无关的基因中（优势比，2.22; 95% CI，1.41 - 3.34），结论我们的研究结果建立了临床外显子组测序的诊断效用，以评估小的基因组变化的作用，死胎新风险信号的强度（通过分层分析产生）与已知疾病基因相似，这表明死产的遗传原因在很大程度上仍然未知。（由基因组医学研究所资助。
BackgroundIn the majority of cases, the cause of stillbirth remains unknown despite detailed clinical and laboratory evaluation. Approximately 10 to 20% of stillbirths are attributed to chromosomal abnormalities. However, the causal nature of single-nucleotide variants and small insertions and deletions in exomes has been understudied.MethodsWe generated exome sequencing data for 246 stillborn cases and followed established guidelines to identify causal variants in disease-associated genes. These genes included those that have been associated with stillbirth and strong candidate genes. We also evaluated the contribution of 18,653 genes in case–control analyses stratified according to the degree of depletion of functional variation (described here as “intolerance” to variation).ResultsWe identified molecular diagnoses in 15 of 246 cases of stillbirth (6.1%) involving seven genes that have been implicated in stillbirth and six disease genes that are good candidates for phenotypic expansion. Among the cases we evaluated, we also found an enrichment of loss-of-function variants in genes that are intolerant to such variation in the human population (odds ratio, 2.15; 95% confidence interval [CI], 1.46 to 3.06). Loss-of-function variants in intolerant genes were concentrated in genes that have not been associated with human disease (odds ratio, 2.22; 95% CI, 1.41 to 3.34), findings that differ from those in two postnatal clinical populations that were also evaluated in this study.ConclusionsOur findings establish the diagnostic utility of clinical exome sequencing to evaluate the role of small genomic changes in stillbirth. The strength of the novel risk signal (as generated through the stratified analysis) was similar to that in known disease genes, which indicates that the genetic cause of stillbirth remains largely unknown. (Funded by the Institute for Genomic Medicine.)