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 associated with Mendelian disease, novel rare variants across the genome, and variants of known pharmacogenomic importance. In addition, we developed an approach to the integration of disease risk across multiple common polymorphisms. Although the methodology is nascent, the results provide a proof-of-principle that clinically meaningful information can be derived about disease risk and the response to medications in patients with whole genome sequence data. A prominent aspect of the patient's family history () is the diagnosis of arrythmogenic right ventricular dysplasia/cardiomyopathy in his first cousin (III-3) and the sudden death of his first cousin once removed (IV-1). Our patient shares 12.5% of his genetic information with his first cousin and 6.25% with that relative's son and, while a diagnostic workup would involve targeted sequencing of DNA from these individuals, our analysis uncovered several variants in genes with potential explanatory value. Most were common variants. One gene (MYBPC3) was previously associated with hypertrophic cardiomyopathy but seems to in fact be a common variant, exemplifying the limitations of current variant databases. Two rare variants in genes (TMEM43, DSP) previously associated with ARVD/C were novel.
Our patient reported a prominent family history of vascular disease including aortic aneurysm and coronary artery disease (, individuals II-1, II-2, I-1, I-2). While it is possible that the collagen variant we found contributes to familial risk of aortic aneurysm, disease in this family is more likely related to atherosclerotic disease. In estimating the risk of coronary artery disease, we integrated the most replicated risk associations, likelihood ratio projections from the entire literature, and a known rare variant in the LPA
gene that may not have been found using chip based genotyping. According to the ATP-III guidelines,24
our patient does not currently have major risk factors for coronary artery disease and would require an LDL > 190 mg/dl to qualify for lipid lowering therapy. However, he is borderline for three major risk factors and any two of these would lower the LDL threshold for treatment to 160 mg/dl (his measured level was 156 mg/dl). Although no standards yet exist for the incorporation of global genetic risk in cardiovascular risk assessment, physicians are accustomed to incorporating many sources of information in clinical decision-making. In this case, the patient's physician took account of this lifetime genetic risk and knowledge of his likely response to therapy into the clinical decision to recommend a lipid lowering medication. Part of this decision focused on the likely response to this therapy. His genome includes variants (Table 3) that predict greater likelihood of beneficial effect for statin medications and lower risk for the adverse effect of skeletal myopathy. In addition, a significant reduction of attributable risk was found in carriers of the LPA
risk allele who took aspirin,20
leading to a discussion between the physician and his patient on the threshold for primary prevention with aspirin therapy. Given a predisposition to coronary artery disease and other diseases on which risk is conditionally dependent (), understanding the patient's potential response to clopidogrel and warfarin may be important aspects of individualising future medical therapy. The patient is at risk for clopidogrel resistance as a result of his CYP2C19
loss of function mutation and his physician recommended a higher dose of clopidogrel in the event of future use or consideration of newer agents with alternative metabolism. In contrast, should the patient develop an indication for warfarin, his genotype at the VKORC1
loci suggests he should take lower initial doses of warfarin. The novel VKORC1 variant may have additional effects on warfarin metabolism.
In contrast, our patient did not report a family history of haemochromatosis or parathyroid tumours yet harbours some genetic risk for these conditions. An important contribution of clinical-genetic risk integration is the appropriate consideration of further screening studies. In addition, risk alleles may be discovered that carry reproductive or familial significance rather than personal significance (such as those for breast or ovarian cancer in a male patient). Appropriate incorporation of such risk alleles into both medical and ethical discussion is warranted.
There remain significant limitations to our ability to comprehensively integrate genetic information into clinical care. For example, there is a lack of a comprehensive rare mutation database or a framework for the statistical combination of risk estimates from multiple common polymorphisms. Since risk estimates change as more studies are completed, a continuously updated pipeline is required. On a technical level, we remain limited in our ability to improve error rates associated with sequencing, in particular, detecting structural variants. Finally, gene-environment interactions are challenging to quantify and have to date been little studied.