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导致死产的遗传变异体
Causal Genetic Variants in Stillbirth


Kate E. Stanley ... 妇产科和儿科 • 2020.08.12
相关阅读
• 死产的遗传学根源分析 • 哪种不良妊娠结局的发生率会随着产妇年龄增长而增加

摘要


背景

大多数病例的死产原因经过详细临床和实验室检查后仍然不明。约有10%~20%的死产可归因于染色体异常。然而,外显子组单核苷酸变异体以及小片段插入和缺失与死产之间的因果关系尚未经过充分研究。

 

方法

我们生成了246个死产病例的外显子组序列数据,并按照现行指南在疾病相关基因中确定了导致死产的变异体。这些基因包括已确定与死产相关的基因和强候选基因(strong candidate gene)。我们还在根据功能性变异减少程度(这里描述为对变异“不耐受”)分层的病例对照分析中评估了18,653个基因的影响。

 

结果

我们在246例死产中确定了15例的分子诊断(6.1%),涉及与死产相关的7个基因,以及属于表型扩展(phenotypic expansion)的好候选基因的6个疾病基因。在我们评估的病例中,我们还发现在人群中,失活变异体在对这些变异不耐受的基因中发生富集(比值比,2.15;95%置信区间[CI],1.46~3.06)。不耐受基因中的失活变异体集中于与人类疾病无关的基因(比值比,2.22;95% CI,1.41~3.34),这一发现与本研究也评估的两个出生后临床人群的情况不同。

 

结论

本研究的结果证实了在评估基因组微小变化对死产产生的影响方面,临床外显子测序的诊断效用。新风险信号(通过分层分析产生)的强度与已知疾病基因相似,这表明导致死产的遗传原因仍大多不明(由基因组医学研究所[Institute for Genomic Medicine]资助)。





作者信息

Kate E. Stanley, B.A., Jessica Giordano, M.S., C.G.C., Vanessa Thorsten, M.P.H., Christie Buchovecky, Ph.D., Amanda Thomas, Ph.D., Mythily Ganapathi, Ph.D., Jun Liao, Ph.D., Avinash V. Dharmadhikari, Ph.D., Anya Revah-Politi, M.S., C.G.C., Michelle Ernst, M.S., C.G.C., Natalie Lippa, M.S., C.G.C., Halie Holmes, M.S., C.G.C., Gundula Povysil, M.D., Ph.D., Joseph Hostyk, B.S., Corette B. Parker, Dr.P.H., Robert Goldenberg, M.D., George R. Saade, M.D., Donald J. Dudley, M.D., Halit Pinar, M.D., Carol Hogue, Ph.D., M.P.H., Uma M. Reddy, M.D., M.P.H., Robert M. Silver, M.D., Vimla Aggarwal, M.B., B.S., Andrew S. Allen, Ph.D., Ronald J. Wapner, M.D., and David B. Goldstein, Ph.D.
From the Institute for Genomic Medicine at Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center (K.E.S., J.G., A.R.-P., M.E., N.L., H.H., G.P., J.H., V.A., R.J.W., D.B.G.), and the Departments of Obstetrics and Gynecology (J.G., R.G., R.J.W.) and Pathology and Cell Biology (C.B., A.T., M.G., J.L., A.V.D., V.A.), Columbia University Medical Center, New York; RTI International, Research Triangle Park (V.T., C.B.P.), and the Department of Biostatistics and Bioinformatics, Duke University, Durham (A.S.A.) — both in North Carolina; the Departments of Obstetrics and Gynecology and Cell Biology, University of Texas Medical Branch, Galveston (G.R.S.); the Division of Maternal–Fetal Medicine, Department of Obstetrics and Gynecology, University of Virginia School of Medicine, Charlottesville (D.J.D.); the Division of Perinatal and Pediatric Pathology, Women and Infants Hospital, Warren Alpert School of Medicine of Brown University, Providence, RI (H.P.); Rollins School of Public Health, Emory University, Atlanta (C.H.); Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Pregnancy and Perinatology Branch, Bethesda, MD (U.M.R.); and the University of Utah and Intermountain Healthcare, Salt Lake City (R.M.S.). Address reprint requests to Dr. Goldstein at the Institute for Genomic Medicine, Hammer Health Sciences, Columbia University Irving Medical Center, 701 W. 168th St., New York, NY 10032, or at dbgoldstein@columbia.edu.

 

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