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
Formation of Chimeric Genes by Copy-Number Variation as a Mutational Mechanism in Schizophrenia
Caitlin Rippey,Tom Walsh,Suleyman Gulsuner,Matt Brodsky,Alexander Nord,Molly Gasperini,Sarah B. Pierce,Cailyn Spurrell,Bradley P. Coe,Niklas Krumm,Ming K. Lee,Jonathan Sebat,Jon McClellan,Mary Claire King +13 more
TL;DR: The results suggest that the formation of chimeric genes is a mechanism by which CNVs contribute to schizophrenia and that, by interfering with parent gene function, chimeras may disrupt critical brain processes, including neurogenesis, neuronal differentiation, and dendritic arborization.
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Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants
Aziz Belkadi,Alexandre Bolze,Yuval Itan,Quentin B. Vincent,Alexander Antipenko,Bertrand Boisson,Jean-Laurent Casanova,Laurent Abel +7 more
TL;DR: Whole-exome sequencing is gradually being optimized to identify mutations in increasing proportions of the protein-coding exome, but whole-genome sequencing (WGS) is becoming an attractive alternative for detecting mutations within WES regions, particularly those due to SNVs.
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Accurate detection of clinically relevant uniparental disomy from exome sequencing data.
TL;DR: UPD can easily be identified using both single and trio ES and may be clinically relevant to patients and should become routine in clinical ES, because it increases the diagnostic yield and could affect genetic counseling.
52
Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction
Dov Tiosano,Dov Tiosano,Hagit N. Baris,Hagit N. Baris,Anlu Chen,Marrit M. Hitzert,Markus Schueler,Federico Gulluni,Antje Wiesener,Antonio Bergua,Adi Mory,Brett Copeland,Joseph G. Gleeson,Joseph G. Gleeson,Patrick Rump,Hester van Meer,Deborah A Sival,Volker Haucke,Josh Kriwinsky,Karl X. Knaup,André Reis,Nadine N. Hauer,Emilio Hirsch,Ronald Roepman,Rolph Pfundt,Christian Thiel,Michael S. Wiesener,Mariam G Aslanyan,David A. Buchner +28 more
TL;DR: The considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe’s syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme.
Detection of structural mosaicism from targeted and whole-genome sequencing data.
Daniel A. King,Alejandro Sifrim,Tomas W Fitzgerald,Raheleh Rahbari,Emma Hobson,Tessa Homfray,Sahar Mansour,Sarju G. Mehta,Mohammed Shehla,Susan Tomkins,Pradeep Vasudevan,Matthew E. Hurles +11 more
TL;DR: A method is presented to detect structural mosaic abnormalities using deviations in allele fraction and read coverage from next-generation sequencing data, applied to patients with undiagnosed developmental disorders, and 11 events among nine patients were detected.
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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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