Clinical assessment incorporating a personal genome.
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.
Ashley
Euan A
EA
Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. euan@stanford.edu
Butte
Atul J
AJ
Wheeler
Matthew T
MT
Chen
Rong
R
Klein
Teri E
TE
Dewey
Frederick E
FE
Dudley
Joel T
JT
Ormond
Kelly E
KE
Pavlovic
Aleksandra
A
Morgan
Alexander A
AA
Pushkarev
Dmitry
D
Neff
Norma F
NF
Hudgins
Louanne
L
Gong
Li
L
Hodges
Laura M
LM
Berlin
Dorit S
DS
Thorn
Caroline F
CF
Sangkuhl
Katrin
K
Hebert
Joan M
JM
Woon
Mark
M
Sagreiya
Hersh
H
Whaley
Ryan
R
Knowles
Joshua W
JW
Chou
Michael F
MF
Thakuria
Joseph V
JV
Rosenbaum
Abraham M
AM
Zaranek
Alexander Wait
AW
Church
George M
GM
Greely
Henry T
HT
Quake
Stephen R
SR
Altman
Russ B
RB
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
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