Elsevier

The Lancet

Volume 375, Issue 9725, 1–7 May 2010, Pages 1525-1535
The Lancet

Articles
Clinical assessment incorporating a personal genome

https://doi.org/10.1016/S0140-6736(10)60452-7Get rights and content

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.

Introduction

Technological advance has greatly reduced the cost of genetic information. However, the explanatory power and path to clinical translation of risk estimates for common variants reported in genome-wide association studies remain unclear. Much of the reason lies in the presence of rare and structural genetic variation. Since we are now able to rapidly and inexpensively sequence complete genomes,1, 2, 3, 4, 5 comprehensive genetic risk assessment and individualisation of treatment might be possible.6 However, present analytical methods are insufficient to make genetic data accessible in a clinical context, and the clinical usefulness of these data for individual patients has not been formally assessed. We aimed to undertake an integrated analysis of a complete human genome in a clinical context.

Section snippets

Patient

A patient with a family history of vascular disease and early sudden death was assessed at Stanford's Center for Inherited Cardiovascular Disease by a cardiologist (EAA) and a board-certified genetic counsellor (KEO). We took the patient's medical history and he was clinically assessed. A four-generation pedigree was drawn. In view of his family history, he underwent electrocardiography, an echocardiogram, and a cardiopulmonary exercise test.

Genome analysis

Technical details of genome sequencing for this

Results

The patient was a 40-year-old man who presented with a family history of coronary artery disease and sudden death. His medical history was not clinically significant and the patient exercised regularly without symptoms. He was taking no prescribed medications and appeared well. Clinical characteristics were within normal limits (table 1). Electrocardiography showed sinus rhythm, normal axis, and high praecordial voltage with early repolarisation. An echocardiogram revealed normal right and left

Discussion

We provide an approach to comprehensive analysis of a human genome in a defined clinical context. We assessed whole-genome genetic risk, focusing on variants in genes that are associated with mendelian disease, novel and rare variants across the genome, and variants of pharmacogenomic importance. Additionally, we developed an approach to the integration of disease risk across several common polymorphisms. Although the methods that we used are nascent, the results provide proof of principle that

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