Clinical assessment incorporating a personal genome

January 01, 0001

Clinical assessment incorporating a personal genome

The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. The researchers from the USA aimed to undertake an integrated analysis of a complete human genome in a clinical context. They 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. They queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. They 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. They also accounted for gene-environment interactions and conditionally dependent risks.

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. They 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.

The researchers concluded: "Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients."

Genome sequencing promised to be relevant for individuals and here we are starting to see it. Outcomes will be fascinating to see.

For the full abstract, click here.

The Lancet 375(9725):1525-1535, 1 May 2010 © Elsevier Ltd 2010
Clinical assessment incorporating a personal genome. Euan A Ashley, Atul J Butte, Matthew T Wheeler et al. Correspondence to Dr Euan Ashley: [email protected]

Category: K. Circulatory. Keywords: clinical, assessment, personal genome, genetic analysis, complete human genome, journal watch.
Synopsis edited by Dr Stephen Wilkinson, Melbourne, Australia. Posted on Global Family Doctor 4 June 2010

Pearls are an independent product of the Cochrane primary care group and are meant for educational use and not to guide clinical care.