Abstract
This book is an ambitious attempt to collate some of the major themes in molecular genetics and how these apply to clinical medicine. However, reading it feels a little bit like reading a manual on the merits of gas lamp lighting just as Thomas Edison was introducing the world to the wonders and applications of electricity.
Any edited book can suffer from a certain lack of coherence with repetition of certain themes and insufficient coverage of other key areas. However, a book focused on molecular genetics published in 2012 that gives only scant consideration of the major revolution of next generation DNA sequencing that is currently transforming the practice of molecular medicine is significantly behind the curve.
Over the past three years, identification of the genes responsible for rare Mendelian disorders has accelerated exponentially, such that it does not seem fanciful to suggest that the underlying causes of all Mendelian disorders will be determined over the next five years. Inherited disorders not amenable to gene discovery previously due to their extreme rarity or sporadic (de novo) nature have been characterized. Initially the new generation sequencing (NGS) platforms were the preserve of large genomic centres undertaking large scale DNA sequencing projects. However, refinements in the applications and footprints mean that research and clinical laboratories around the world are investing in them. Soon they will replace Sanger sequencing platforms in all laboratories. Clinical genetics laboratories in the UK, USA and across Europe are already employing NGS to screen large panels of genes in conditions with significant heterogeneity, including deafness, retinal disorders, cardiomyopathy and cancer. These conditions provided a real challenge using previous techniques as each gene would require sequencing independently resulting in significant costs and delays in generating results. A number of groups are developing the capacity to sequence entire exomes (the 1% of the human genome that encodes proteins) as a clinical service. It is envisaged that this will be available routinely in the next couple of years. This approach has significant advantages – a single test pipeline that is able to screen for the cause of any inherited disorder, but raises concerns about generating co-incidental information, potentially indicating risk of a previously unsuspected disorder and challenges in terms of data storage and complex interpretation. NGS will also be able to characterize chromosomal disorders, replacing microarrays and standard karyotyping. NGS is not a panacea and deficiencies exist which need to be addressed but the investment by the commercial and academic worlds mean that these will be surmounted.
The excellent chapter on somatic mutations in cancer also does not consider that NGS is defining novel driver and passenger mutations, transforming understanding of the molecular basis of cancer origin and progression. A number of clinical laboratories are already providing testing of multiple genes relevant to the choice of the optimum targeted treatment in cancer. Even these multiplex genotyping strategies are likely to be superseded by NGS over the next few years.
As a summary of the world of molecular genetics in the noughties this book works well. However, for any reader less interested in history and more in the future new world of genetic medicine it falls short.