PHG Foundation | Clinical analysis of a whole genome

Clinical analysis of a whole genome
30 April 2010 | By Dr Caroline Wright and Dr Philippa Brice | Research article

A new paper in the Lancet provides the first example of a full-genome sequence of a healthy individual being combined with a broad clinical analysis [Ashley EA et al. Lancet (2010) 375: 1525-35]. Although the genome sequence was published last year (see previous news), the “comprehensive” clinical work-up is new.

Unlike the previous examples of clinical whole genome sequencing, which involved families with specific rare genetic disorders (see previous news), the focus of this study is a healthy man with a family history of vascular disease and early sudden (presumed cardiac) death. In addition, rather than focusing on a single condition, or even a single type of condition, this study tries to extract as much clinically relevant information as possible from the genome relating to any kind of disease predisposition. Researchers used so-called third generation (single molecule) sequencing technology for sequencing the entire genome; in addition, a subset of single nucleotide polymorphisms (SNPs) were independently validated using a standard SNP-array and some variants were confirmed using traditional Sanger sequencing. Various online databases were used to screen for variants of clinical relevance, and the findings include information about genetic susceptibility to common complex diseases, pharmacogenetic information that could inform drug choice and dose, and information about variants in genes associated with inherited cardiac conditions that can predispose to sudden cardiac death.

Comment: This is an exemplar of the sort of approach that will become increasingly feasible in the future as the costs of genome sequencing continue to fall. The authors state that “an important benefit of sequencing compared with DNA chip-based methods of genotyping is the identification of rare or novel variants”. While true, this benefit is actually a double-edged sword: almost by definition, it will often be extremely difficult to determine the effect of rare and novel variants on the phenotype. Even where a novel variant is present in a gene of known function, which has been linked to a Mendelian disease, the effect of that specific variant upon either the encoded protein, the individual’s physiology, or their overall phenotype may still be impossible to determine. Hence, deriving clinically actionable information may often not be possible.

The analysis of common variants and their implications for increased genetic risk to a range of common complex diseases is certainly admirable for the clarity and transparent manner in which the information is displayed. However, there are serious concerns about the validity (and utility) of using these common variants to predict disease risk in an individual (see, for example, previous news); in addition, questions remain over the long-term effectiveness of using genetic information to motivate behaviour change.

The paper highlights a range of issues that require urgent consideration as full-genome sequencing moves towards reality in medical practice. Evaluation of clinical utility – distinguishing between genuinely useful and irrelevant, misleading or even harmful genetic information – will be crucial, taking into account the complexity of combining genetic data with other clinical and risk information such as family history, markers of current health and lifestyle or environmental factors. Dealing with ‘incidental’ or unintended findings will also be critical, and determining how far the duty of care extends, both within and between overlapping clinical specialties, may dictate the boundaries for medical negligence. Prompt action is needed to consider how health services should be preparing for the onset of whole genome-sequencing as a clinical tool, including such areas as the development of the necessary bioinformatic and IT systems, consideration of the wider ethical, societal and regulatory issues related to the more extensive use and storage of personal genomic information, and development of a health professional workforce with the necessary knowledge and skills to capitalise upon the benefits of next generation whole genome sequencing technologies (see Guardian news article...
PHG Foundation | Clinical analysis of a whole genome