title: Clinical assessment incorporating a personal genome.
abstract: BACKGROUND
  The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context.
  
  
  METHODS
  We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks.
  
  
  RESULTS
  Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported.
  
  
  CONCLUSIONS
  Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients.
  
  
  BACKGROUND
  National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation.
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. euan@stanford.edu
authors.forename: Euan A
authors.initials: EA
authors.lastname: Ashley
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Wheeler
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Teri E
authors.initials: TE
authors.lastname: Klein
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Dewey
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dudley
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Ormond
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pavlovic
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Morgan
authors.forename: Dmitry
authors.initials: D
authors.lastname: Pushkarev
authors.forename: Norma F
authors.initials: NF
authors.lastname: Neff
authors.forename: Louanne
authors.initials: L
authors.lastname: Hudgins
authors.forename: Li
authors.initials: L
authors.lastname: Gong
authors.forename: Laura M
authors.initials: LM
authors.lastname: Hodges
authors.forename: Dorit S
authors.initials: DS
authors.lastname: Berlin
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Thorn
authors.forename: Katrin
authors.initials: K
authors.lastname: Sangkuhl
authors.forename: Joan M
authors.initials: JM
authors.lastname: Hebert
authors.forename: Mark
authors.initials: M
authors.lastname: Woon
authors.forename: Hersh
authors.initials: H
authors.lastname: Sagreiya
authors.forename: Ryan
authors.initials: R
authors.lastname: Whaley
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Knowles
authors.forename: Michael F
authors.initials: MF
authors.lastname: Chou
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Thakuria
authors.forename: Abraham M
authors.initials: AM
authors.lastname: Rosenbaum
authors.forename: Alexander Wait
authors.initials: AW
authors.lastname: Zaranek
authors.forename: George M
authors.initials: GM
authors.lastname: Church
authors.forename: Henry T
authors.initials: HT
authors.lastname: Greely
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Quake
authors.forename: Russ B
authors.initials: RB
authors.lastname: Altman
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D016757:Death, Sudden, Cardiac; D051180:Desmoplakins / Q000235:genetics; D004777:Environment; D005192:Family Health; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D015894:Genome, Human; D006801:Humans; D017270:Lipoprotein(a) / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D006899:Mixed Function Oxygenases / Q000235:genetics; D009154:Mutation; D010003:Osteoarthritis / Q000235:genetics; D010375:Pedigree; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D017422:Sequence Analysis, DNA; D014652:Vascular Diseases / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases; D000099163:Myosin Binding Protein C
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D002352:Carrier Proteins; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; D051180:Desmoplakins; D017270:Lipoprotein(a); D008565:Membrane Proteins; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D000099163:Myosin Binding Protein C; C495294:DSP protein, human; C528696:TMEM43 protein, human; C045793:CYP2C19 protein, human; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human