Clinical assessment incorporating a personal genome

The Lancet, Volume 375, Issue 9725, Pages 1525 - 1535, 1 May 2010 doi:10.1016/S0140-6736(10)60452-7Cite or Link Using DOI
Clinical assessment incorporating a personal genome

Dr Euan A Ashley MRCP a , Atul J Butte MD e, Matthew T Wheeler MD a, Rong Chen PhD e, Teri E Klein PhD g, Frederick E Dewey MD a, Joel T Dudley e, Kelly E Ormond MSc g, Aleksandra Pavlovic BS a, Alexander A Morgan MS e, Dmitry Pushkarev c f, Norma F Neff PhD c f, Prof Louanne Hudgins MD d, Li Gong PhD g, Laura M Hodges PhD g, Dorit S Berlin PhD g, Caroline F Thorn PhD g, Katrin Sangkuhl PhD g, Joan M Hebert MA g, Mark Woon BSE g, Hersh Sagreiya g, Ryan Whaley BS g, Joshua W Knowles MD a, Michael F Chou PhD j, Joseph V Thakuria MD i j, Abraham M Rosenbaum PhD j, Alexander Wait Zaranek PhD j, George M Church PhD j, Prof Henry T Greely JD h, Stephen R Quake PhD c f, Prof Russ B Altman MD b c g
Summary

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.

Findings
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.

Interpretation
Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients.

Funding
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.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60452-7/abstract