Copy number variation detection and genotyping from exome sequence data
Niklas Krumm,Peter H. Sudmant,Arthur Ko,Brian J. O'Roak,Maika Malig,Bradley P. Coe,Aaron R. Quinlan,Deborah A. Nickerson,Evan E. Eichler +8 more
TL;DR: A novel method using singular value decomposition (SVD) normalization to discover rare genic copy number variants (CNVs) as well as genotype copy number polymorphic (CNP) loci with high sensitivity and specificity from exome sequencing data is developed.
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Abstract: While exome sequencing is readily amenable to single-nucleotide variant discovery, the sparse and nonuniform nature of the exome capture reaction has hindered exome-based detection and characterization of genic copy number variation. We developed a novel method using singular value decomposition (SVD) normalization to discover rare genic copy number variants (CNVs) as well as genotype copy number polymorphic (CNP) loci with high sensitivity and specificity from exome sequencing data. We estimate the precision of our algorithm using 122 trios (366 exomes) and show that this method can be used to reliably predict (94% overall precision) both de novo and inherited rare CNVs involving three or more consecutive exons. We demonstrate that exome-based genotyping of CNPs strongly correlates with whole-genome data (median r(2) = 0.91), especially for loci with fewer than eight copies, and can estimate the absolute copy number of multi-allelic genes with high accuracy (78% call level). The resulting user-friendly computational pipeline, CoNIFER (copy number inference from exome reads), can reliably be used to discover disruptive genic CNVs missed by standard approaches and should have broad application in human genetic studies of disease.
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Citations
Using XHMM software to detect copy number variation in whole-exome sequencing data
TL;DR: This unit gives detailed instructions on how to run XHMM and how to use the resulting CNV calls in biological analyses, including sorting out signal from noise, for which a set of statistical and computational tools calledXHMM has recently been developed.
Mutations in PIEZO2 Cause Gordon Syndrome, Marden-Walker Syndrome, and Distal Arthrogryposis Type 5
Margaret J. McMillin,Anita E. Beck,Anita E. Beck,Jessica X. Chong,Kathryn M. Shively,Kati J. Buckingham,Heidi I. S. Gildersleeve,Mariana Aracena,Arthur S. Aylsworth,Pierre Bitoun,John C. Carey,Carol L. Clericuzio,Yanick J. Crow,Cynthia J. Curry,Koenraad Devriendt,David B. Everman,Alan Fryer,Kate Gibson,Maria Luisa Giovannucci Uzielli,John M. Graham,Judith G. Hall,Jacqueline T. Hecht,Randall A. Heidenreich,Jane A. Hurst,Sarosh R. Irani,Ingrid P.C. Krapels,Jules G. Leroy,David Mowat,David Mowat,Gordon T. Plant,Stephen P. Robertson,Elizabeth K. Schorry,Richard H Scott,Laurie H. Seaver,Elliott H. Sherr,Miranda Splitt,Helen Stewart,Constance T. R. M. Stumpel,Sehime Gulsun Temel,Sehime Gulsun Temel,David D. Weaver,Margo Whiteford,Marc S. Williams,Holly K. Tabor,Joshua D. Smith,Jay Shendure,Deborah A. Nickerson,Michael J. Bamshad,Michael J. Bamshad +48 more
TL;DR: Findings indicate that GS, DA5, and MWS have traditionally been considered separate disorders, are etiologically related and perhaps represent variable expressivity of the same condition.
Human Genome Sequencing at the Population Scale: A Primer on High-Throughput DNA Sequencing and Analysis.
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Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere's disease
Teresa Requena,Sonia Cabrera,Carmen Martín-Sierra,Steven D. Price,Anna Lysakowski,Jose A. Lopez-Escamez +5 more
TL;DR: By whole-exome sequencing, two novel heterozygous single-nucleotide variants in FAM136A and DTNA genes are identified, both in a Spanish family with three affected cases in consecutive generations, highly suggestive of autosomal-dominant inheritance.
Genomic analysis of inherited hearing loss in the Palestinian population.
Amal Abu Rayyan,Amal Abu Rayyan,Lara Kamal,Silvia Casadei,Zippora Brownstein,Fouad Zahdeh,Hashem Shahin,Christina Canavati,Dima Dweik,Tamara Jaraysa,Grace Rabie,Ryan J. Carlson,Suleyman Gulsuner,Ming K. Lee,Karen B. Avraham,Tom Walsh,Mary Claire King,Moien Kanaan +17 more
TL;DR: For the great majority of families with inherited hearing loss, panel-based genomic DNA sequencing, followed by segregation analysis of large kindreds and transcriptional analysis of participant RNA, enabled identification of the causal genes and mutations, including at distant noncoding sites.
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Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
Brian J. O'Roak,Laura Vives,Santhosh Girirajan,Emre Karakoc,Niklas Krumm,Bradley P. Coe,Roie Levy,Arthur Ko,Choli Lee,Joshua D. Smith,Emily H. Turner,Ian B. Stanaway,Benjamin Vernot,Maika Malig,Carl Baker,Beau Reilly,Joshua M. Akey,Elhanan Borenstein,Elhanan Borenstein,Mark J. Rieder,Deborah A. Nickerson,Raphael Bernier,Jay Shendure,Evan E. Eichler,Evan E. Eichler +24 more
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