Journal article
Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios
Xiaolin Zhu, Slave Petrovski, Pingxing Xie, Elizabeth K Ruzzo, Yi-Fan Lu, K Melodi McSweeney, Bruria Ben-Zeev, Andreea Nissenkorn, Yair Anikster, Danit Oz-Levi, Ryan S Dhindsa, Yuki Hitomi, Kelly Schoch, Rebecca C Spillmann, Gali Heimer, Dina Marek-Yagel, Michal Tzadok, Yujun Han, Gordon Worley, Jennifer Goldstein Show all
GENETICS IN MEDICINE | NATURE PUBLISHING GROUP | Published : 2015
DOI: 10.1038/gim.2014.191
Abstract
PURPOSE: Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene-disease associations. METHODS: We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of pat..
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Grants
Awarded by Bryan ADRC NIA
Awarded by Ellison Medical Foundation New Scholar award
Awarded by SAIC-Frederick
Awarded by NIMH awards
Awarded by Epi4K Gene Discovery in Epilepsy study (NINDS)
Awarded by Epilepsy Genome/Phenome Project (EPGP - NINDS)
Awarded by Center for HIV/AIDS Vaccine Immunology ("CHAVI") under National Institute of Allergy and Infectious Diseases, National Institutes of Health
Awarded by NIMH grant
Awarded by Swedish Research Council
Awarded by NIMH Grand Opportunity grant
Awarded by NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
Awarded by NATIONAL INSTITUTE OF MENTAL HEALTH
Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Awarded by NATIONAL INSTITUTE ON AGING
Funding Acknowledgements
We appreciate all the patients, their parents, the clinical research coordinators, and the referring physicians for participating in this study. We thank B. Krueger, J. Bridgers, J. Keebler, Z. Ren, and Q. Wang for bioinformatics support. We thank K. Cronin, S. Shaltz, A. Richards, and N. Walley for excellent technical support. The authors thank the National Heart, Lung, and Blood Institute Grand Opportunity (GO) Exome Sequencing Project and its ongoing studies that produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL102923); the WHI Sequencing Project (HL-102924); the Broad GO Sequencing Project (HL-102925); the Seattle GO Sequencing Project (HL-102926); and the Heart GO Sequencing Project (HL103010). S.P. is a National Health and Medical Research Council CJ Martin Fellow. We acknowledge the following individuals for the contributions of control samples: W.B. Gallentine, E.L. Heinzen, A.M. Husain, K.N. Linney, M.A. Mikati, R.A. Radtke, and S.R. Sinha; J.P. McEvoy, J. Silver, and M. Silver; D.H. Murdock and The MURDOCK Study Community Registry and Biorepository; G. Cavalleri, N. Delanty, and C. Depondt; J. Burke, C. Hulette, and K. Welsh-Bohmer; J. Milner; J. Hoover-Fong, N.L. Sobreira, and D. Valle; E.J. Holtzman; W.L. Lowe; P. Lugar; S.M. Palmer; Z. Farfel, A. Poduri; M. Hauser; D. Marchuk; D. Koltai Attix, O. Chiba-Falek; E.T. Cirulli, V. Dixon, and J. McEvoy; K. Schmader, S. McDonald, H.K. White, M. Yanamadala, and the Carol Woods and Crosdaile Retirement Communities; R. Gbadegesin and M. Winn; D. Daskalakis; Q. Zhao; A. Holden, and E. Behr; R. Brown; and S. Kerns and H. Oster. The collection of control samples was funded in part by Bryan ADRC NIA P30 AG028377, the Ellison Medical Foundation New Scholar award AG-NS-0441-08, an award from SAIC-Frederick (M11-074), funding from Biogen Idec, NIMH awards RC2MH089915, R01MH097971, R01MH099216, and K01MH098126, the Epi4K Gene Discovery in Epilepsy study (NINDS U01-NS077303), the Epilepsy Genome/Phenome Project (EPGP - NINDS U01-NS053998), and the Center for HIV/AIDS Vaccine Immunology ("CHAVI") under a grant from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (UO1AIO67854). E.K.R is funded by a predoctoral grant from the Epilepsy Foundation and Jo Rae Wright Fellowship for outstanding women in science (Duke University). Additional control samples were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through accession number phs000473. Samples used for data analysis were provided by the Swedish Cohort Collection supported by the NIMH grant R01MH077139, the Sylvan C. Herman Foundation, the Stanley Medical Research Institute, and the Swedish Research Council (grants 2009-4959 and 2011-4659). Support for the exome sequencing was provided by the NIMH Grand Opportunity grant RCMH089905, the Sylvan C. Herman Foundation, a grant from the Stanley Medical Research Institute, and multiple gifts to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard.