title: Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data.
abstract: High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.
authors.affiliation: Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, California, United States of America; Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America; Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America.
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Dewey
authors.affiliation: Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, California, United States of America; Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America; Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Grove
authors.affiliation: Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, California, United States of America; Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America; Division of Pediatric Cardiology, Stanford University, Stanford, California, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Priest
authors.affiliation: Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, California, United States of America; Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America.
authors.forename: Daryl
authors.initials: D
authors.lastname: Waggott
authors.affiliation: Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, California, United States of America; Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America.
authors.forename: Prag
authors.initials: P
authors.lastname: Batra
authors.affiliation: Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America; Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America.
authors.forename: Clint L
authors.initials: CL
authors.lastname: Miller
authors.affiliation: Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, California, United States of America; Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America; Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wheeler
authors.affiliation: Stanford Center for Genomics and Personalized Medicine, Stanford University, Stanford, California, United States of America; Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Amin
authors.initials: A
authors.lastname: Zia
authors.affiliation: Stanford Center for Genomics and Personalized Medicine, Stanford University, Stanford, California, United States of America; Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Cuiping
authors.initials: C
authors.lastname: Pan
authors.affiliation: Stanford Center for Genomics and Personalized Medicine, Stanford University, Stanford, California, United States of America; Department of Genetics, Stanford University, Stanford, California, United States of America; Biomedical Informatics Training Program, Stanford University, Stanford, California, United States of America.
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Karzcewski
authors.affiliation: Division of Pediatric Cardiology, Stanford University, Stanford, California, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Miyake
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Whirl-Carrillo
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Teri E
authors.initials: TE
authors.lastname: Klein
authors.affiliation: Stanford Center for Genomics and Personalized Medicine, Stanford University, Stanford, California, United States of America.
authors.forename: Somalee
authors.initials: S
authors.lastname: Datta
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Russ B
authors.initials: RB
authors.lastname: Altman
authors.affiliation: Stanford Center for Genomics and Personalized Medicine, Stanford University, Stanford, California, United States of America; Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America; Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.affiliation: Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, California, United States of America; Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America; Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America; Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Euan A
authors.initials: EA
authors.lastname: Ashley
mesh_terms: D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002874:Chromosome Mapping; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D010641:Phenotype; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C507517:ATP2B4 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases