- Carrier Testing for Severe Childhood...

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DOI: 10.1126/scitranslmed.3001756 , 65ra4 (2011); 3 Sci Transl Med , et al. Callum J. Bell Next-Generation Sequencing Carrier Testing for Severe Childhood Recessive Diseases by can be found at: and other services, including high-resolution figures, A complete electronic version of this article can be found in the online version of this article at: Supplementary Material can be found online at: Related Resources for this article , 13 of which can be accessed free: cites 54 articles This article 1 articles hosted by HighWire Press; see: cited by This article has been in whole or in part can be found at: article permission to reproduce this of this article or about obtaining reprints Information about obtaining is a registered trademark of AAAS. Science Translational Medicine rights reserved. The title NW, Washington, DC 20005. Copyright 2011 by the American Association for the Advancement of Science; all last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue (print ISSN 1946-6234; online ISSN 1946-6242) is published weekly, except the Science Translational Medicine on January 13, 2011 Downloaded from
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HUMAN GENOMICS Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing Callum J. Bell, 1 * Darrell L. Dinwiddie, 1,2 * Neil A. Miller, 1,2 Shannon L. Hateley, 1 Elena E. Ganusova, 1 Joann Mudge, 1 Ray J. Langley, 1 Lu Zhang, 3 Clarence C. Lee, 4 Faye D. Schilkey, 1 Vrunda Sheth, 4 Jimmy E. Woodward, 1 Heather E. Peckham, 4 Gary P. Schroth, 3 Ryan W. Kim, 1 Stephen F. Kingsmore 1,2 Of 7028 disorders with suspected Mendelian inheritance, 1139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases collectively account for ~20% of infant mortality and ~10% of pediatric hospitalizations. Preconception screening, together with genetic counseling of carriers, has re- sulted in remarkable declines in the incidence of several severe recessive diseases including Tay-Sachs disease and cystic fibrosis. However, extension of preconception screening to most severe disease genes has hitherto been impractical. Here, we report a preconception carrier screen for 448 severe recessive childhood diseases. Rather than costly, complete sequencing of the human genome, 7717 regions from 437 target genes were enriched by hybrid capture or microdroplet polymerase chain reaction, sequenced by next-generation sequencing (NGS) to a depth of up to 2.7 gigabases, and assessed with stringent bioinformatic filters. At a resultant 160× average target coverage, 93% of nucleotides had at least 20× coverage, and mutation detection/genotyping had ~95% sensitivity and ~100% specificity for substitution, insertion/deletion, splicing, and gross deletion mutations and single-nucleotide polymorphisms. In 104 unrelated DNA samples, the average genomic carrier burden for severe
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