• Kate E Stanley, Jessica Giordano, Vanessa Thorsten, Christie Buchovecky, Amanda Thomas, Mythily Ganapathi, Jun Liao, Avinash V Dharmadhikari, Anya Revah-Politi, Michelle Ernst, Natalie Lippa, Halie Holmes, Gundula Povysil, Joseph Hostyk, Corette B Parker, Robert Goldenberg, George R Saade, Donald J Dudley, Halit Pinar, Carol Hogue, Uma M Reddy, Robert M Silver, Vimla Aggarwal, Andrew S Allen, Ronald J Wapner, and David B Goldstein.
• 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.).
• N. Engl. J. Med. 2020 Sep 17; 383 (12): 110711161107-1116.

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.).Copyright © 2020 Massachusetts Medical Society.

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