Today, more than ever before, a staggering array of new diagnostic options exist to enable accurate genetic diagnosis of genetic conditions. This has been made possible by quantum leaps in computing, which have allowed rapid, interpretable screening of our entire coding DNA sequences and our full genomes at exponentially-affordable prices. We have now reached a tipping point where single gene testing is becoming less practical and less frequent than such multiple gene testing, especially as most diseases are caused by many different genes. It now makes more common and economic sense to screen all the known genes that can cause a particular disorder, such as retinitis pigmentosa (a degenerative eye disease) than to screen each known gene individually.
These new technologies are enabling patients with hitherto undiagnosed constellations of symptoms and signs, to have the genetic basis of their disorders worked out. This trend will only get stronger as the gap between genetic data and consequent useful clinical information is bridged. In this prevailing environment, it is not hard to predict that in the near future, the vast majority of patients with genetic diseases will have the specific gene sequences associated with their condition confirmed. This should, in turn, lay foundations for documenting the clinical history of the patient associated with their specific DNA sequence differences. This will provide predictive tests (including those conduced prenatally) and diagnostic tests for relatives at risk, and most importantly, an understanding of the causes and mechanisms of the condition.
This last consequence is crucial as it provides a pathway to treatment of a genetic disorder based on the way it developed. The linchpin underlying treatment of infectious disease for decades, it is only now that we possess the tools to apply this to combat genetic diseases. Effective treatment for genetic conditions based on their underlying cause is now science reality, not fiction. Examples of how our knowledge of diseases in which discovery of specific disrupted genes have allowed us to treat that disease include tuberous sclerosis, a rare genetic disease that causes benign tumors to grow in many organs1; Marfan syndrome2, a genetic disorder that affects the body’s connective tissue; age-related macular degeneration, a common eye condition and a leading cause of loss of vision in those over 503, and hypophosphatasia, an inherited disorder that affects the development of bones and teeth4. These examples all show how the development of new disease treatments based on knowledge about specific genetic mechanisms. They are game- and life-changers in the management of genetic conditions, giving patients and families new treatment options and health outcomes.
If we are to move swiftly to an era of genetic medicine aimed at each individual, it is vital that effective, quick, and robust pathways are established, leading from the diagnosis of a genetic condition to the identification of biologically plausible treatments. This will involve discussion between doctors, basic scientists, funding bodies (government and non-government), and industry to ensure the advances made in diagnosis of genetic diseases can be translated to better treatments quickly, through good clinical trials.
With a shortfall of public research funding worldwide, policy reform is required to ensure research that spans the breach between diagnosis and intervention in genetic disease is prioritised.
As the way in which we think about genetic diagnosis and treatment are transformed, it will be prudent to reset research goals and, before attempting to unravel the ‘A-to-Z’ of a condition, first discover its ‘D-to-I’ (diagnosis to intervention) pathway.
Krueger DA, Care MM, Holland K, Agricola K et al., Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363:1801-11, 2010.
Brooke BS, Habashi JP, Judge DP, Patel N et al., Angiotensin II blockade and aortic-root dilatation in Marfan syndrome. N Engl J Med 358:2787-95, 2008.
Xu D and Kaiser PK. Intravitreal aflibercept for neovascular age-related macular degeneration. Immunotherapy 5:121-30, 2013.
Whyte MP, Greenberg CR, Salman NJ, Bober MB et al., Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med 366:904-13, 2012.
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