Clinical whole-exome sequencing for the diagnosis of mendelian disorders.
Yaping Yang,Donna M. Muzny,Jeffrey G. Reid,Matthew N. Bainbridge,Alecia Willis,Patricia A. Ward,Alicia Braxton,Joke Beuten,Fan Xia,Zhiyv Niu,Matthew T. Hardison,Richard E. Person,Mir Reza Bekheirnia,Magalie S. Leduc,Amelia Kirby,Peter Pham,Jennifer Scull,Min Wang,Yan Ding,Sharon E. Plon,James R. Lupski,Arthur L. Beaudet,Richard A. Gibbs,Christine M. Eng +23 more
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W whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition.Abstract:
Background Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders. Methods We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients. Results We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic phenotypes. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had autosomal recessive disease, and 9 had X-linked disease. A total of 4 probands re...read more
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REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants
Nilah M. Ioannidis,Joseph H. Rothstein,Joseph H. Rothstein,Vikas Pejaver,Sumit Middha,Shannon K. McDonnell,Saurabh Baheti,Anthony M. Musolf,Qing Li,Emily R. Holzinger,Danielle M. Karyadi,Lisa A. Cannon-Albright,Craig C. Teerlink,Janet L. Stanford,William B. Isaacs,Jianfeng Xu,Kathleen A. Cooney,Kathleen A. Cooney,Ethan M. Lange,Johanna Schleutker,John D. Carpten,Isaac J. Powell,Olivier Cussenot,Geraldine Cancel-Tassin,Graham G. Giles,Graham G. Giles,Robert J. MacInnis,Robert J. MacInnis,Christiane Maier,Chih-Lin Hsieh,Fredrik Wiklund,William J. Catalona,William D. Foulkes,Diptasri Mandal,Rosalind A. Eeles,Zsofia Kote-Jarai,Carlos Bustamante,Daniel J. Schaid,Trevor Hastie,Elaine A. Ostrander,Joan E. Bailey-Wilson,Predrag Radivojac,Stephen N. Thibodeau,Alice S. Whittemore,Weiva Sieh,Weiva Sieh +45 more
TL;DR: This work developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, LRT, GERP, SiPhy, phyloP, and phastCons.
Journal ArticleDOI
Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing
Yaping Yang,Donna M. Muzny,Fan Xia,Zhiyv Niu,Richard E. Person,Yan Ding,Patricia A. Ward,Alicia Braxton,Min Wang,Christian J. Buhay,Narayanan Veeraraghavan,Alicia Hawes,Theodore Chiang,Magalie S. Leduc,Joke Beuten,Jing Zhang,Weimin He,Jennifer Scull,Alecia Willis,Megan Landsverk,William J. Craigen,Mir Reza Bekheirnia,Asbjørg Stray-Pedersen,Pengfei Liu,Shu Wen,Wendy Alcaraz,Hong Cui,Magdalena Walkiewicz,Jeffrey G. Reid,Matthew N. Bainbridge,Ankita Patel,Eric Boerwinkle,Eric Boerwinkle,Arthur L. Beaudet,James R. Lupski,Sharon E. Plon,Richard A. Gibbs,Christine M. Eng +37 more
TL;DR: Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease, and may offer advantages over traditional molecular diagnostic approaches in certain patients.
Journal ArticleDOI
High-Throughput Sequencing Technologies
TL;DR: In this article, the authors discuss commonly used high-throughput sequencing platforms, the growing array of sequencing assays developed around them, as well as the challenges facing current sequencing platforms and their clinical application.
Journal ArticleDOI
Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders
Hane Lee,Joshua L. Deignan,Naghmeh Dorrani,Samuel P. Strom,Sibel Kantarci,Fabiola Quintero-Rivera,Kingshuk Das,Traci Toy,Bret Harry,Michael Yourshaw,Michelle Fox,Brent L. Fogel,Julian A. Martinez-Agosto,Derek Wong,Vivian Y. Chang,Perry B. Shieh,Christina G.S. Palmer,Katrina M. Dipple,Wayne W. Grody,Eric Vilain,Stanley F. Nelson +20 more
TL;DR: Initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types are reported, and trio-CES was associated with higher molecular diagnostic yield than proband-Ces or traditional molecular diagnostic methods.
Journal ArticleDOI
Clinical application of whole-exome sequencing across clinical indications.
Kyle Retterer,Jane Juusola,Megan T. Cho,Patrik Vitazka,Francisca Millan,Federica Gibellini,Annette Vertino-Bell,Nizar Smaoui,Nizar Smaoui,Julie Neidich,Kristin G. Monaghan,Dianalee McKnight,Renkui Bai,Sharon F. Suchy,Bethany Friedman,Jackie Tahiliani,Daniel E. Pineda-Alvarez,Gabriele Richard,Tracy Brandt,Eden Haverfield,Wendy K. Chung,Sherri J. Bale +21 more
TL;DR: The experience with the first 3,040 WES cases suggests that analysis of trios significantly improves the diagnostic yield compared with proband-only testing for genetically heterogeneous disorders and facilitates identification of novel candidate genes.
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TL;DR: It is recommended that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here and encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.
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