Articles
Clinical assessment incorporating a personal genome
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
References (54)
- et al.
Massively parallel sequencing: the next big thing in genetic medicine
Am J Hum Genet
(2009) - et al.
Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy
Atherosclerosis
(2009) - et al.
A homozygous nonsense mutation in the beta 3 chain gene of laminin 5 (LAMB3) in Herlitz junctional epidermolysis bullosa
Genomics
(1994) - et al.
Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations
J Am Coll Cardiol
(2001) - et al.
Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden
J Mol Cell Cardiol
(2003) - et al.
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy
J Am Coll Cardiol
(2004) - et al.
Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene
Am J Hum Genet
(2008) - et al.
Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy
Blood
(2009) - et al.
CYP4F2 genetic variant alters required warfarin dose
Blood
(2008) - et al.
Genetic diagnosis by whole exome capture and massively parallel DNA sequencing
Proc Natl Acad Sci USA
(2009)