The Human Genome Project was founded on the premise that it would unlock the secrets of disease and lead to new cures for many disorders. While the new cures have mostly yet to materialise, the secrets of disease are indeed being revealed, in ways that will transform medicine over the coming years. Both our knowledge of the genetic causes of disease and our ability to test for those causes have increased exponentially in recent years. These advances will place genetic testing at the front line of diagnostics, not just for the relatively small number of already well-known inherited disorders, but for an ever-widening array of conditions, both rare and common.
The lifetime prevalence of rare disorders in European populations is estimated at 6-8% of the population (National Rare Disease Plan for Ireland, 2014-2018). Over 6,000 distinct genetic disorders are already defined and more are being discovered at an increasing pace. For many patients with such disorders, their experience with the health system involves a long and frustrating diagnostic odyssey. They are typically seen by various specialists for various symptoms, but the connections between them are not always recognised. A referral for genetic testing may be made eventually, but usually as a last resort rather than a first option.
In a growing proportion of such cases, genetic testing can reveal the underlying cause of the condition, bringing certainty and insight to the diagnosis. While specific medications may not exist that target each condition, a genetic diagnosis can often provide useful predictions of prognosis and treatment responsiveness. This is especially true for the hundreds of metabolic disorders, which may be treatable by dietary interventions or supplements.
But even in cases where there are no direct medical implications, just receiving a specific diagnosis can be highly beneficial in helping patients and their families cope with the situation. In addition, many international support groups have arisen relating to specific disorders, or for rare diseases in general, such as NORD (U.S.), GRDO (Ireland) and Rare Disease UK. These organisations are helping patients, parents and clinicians share information, compare experiences and improve outcomes. Genetic information can also inform future reproductive decisions, including possibilities such as pre-implantation genetic screening.
Rare mutations can cause common disorders
The effects of genetic mutations are not restricted to what we typically think of as rare disorders, however. Discoveries over the last several years are illustrating their central role in much more common disorders, such as epilepsy, autism, schizophrenia, Alzheimer’s and Parkinson’s disease, many cancers and other conditions. Indeed, many of those diagnostic categories may in fact be umbrella terms for a multiplicity of rare disorders that manifest with similar symptoms.
For neuropsychiatric conditions, it has long been known that such disorders are highly heritable, but it had not been possible to identify causal genes. That has changed, with the development of new DNA sequencing technologies, yielding insights that overturn our conception of such disorders. Rather than reflecting a single entity, broad clinical categories like autism or epilepsy obscure an extreme diversity of underlying conditions. Each of these conditions may be quite rare but there are so many of them that manifest in similar ways that collectively they result in highly prevalent disorders. Genetics now provides the tools to distinguish them.
The causal mutations in patients with these conditions can disrupt single genes or can delete or duplicate small sections of chromosomes, affecting multiple genes at once. For very severe cases, the mutations will often have arisen de novo, in the generation of egg or, more commonly, sperm cells. But others are inherited, often from parents who are clinically unaffected, despite carrying the mutation. This highlights the complexity in relating genotypes to phenotypes – the clinical presentation of such mutations is quite variable and often depends on other genetic or environmental factors. Nevertheless, in a patient showing symptoms, the identification of a major mutation can reveal important information as to the primary cause.
For example, for patients with a diagnosis of autism – a diagnosis based on symptoms alone – genetic testing for specific conditions like Fragile X syndrome or Rett syndrome has been in place for some time. This is now being expanded to include testing for a growing number of chromosomal disorders or single-gene mutations, which collectively can now explain ~15% of cases – a huge increase from just a few years ago. This percentage is growing all the time as causal mutations in new genes are identified (reaching 20-25% in recent studies). The successes for autism are likely to be duplicated for other conditions as the number of sequenced patient genomes increases.
Genome sequencing now an affordable front-line option
The pace of technological change in this field is simply staggering. We are moving from acan be sequenced for under $2,000, in about a day, maybe two.
Those sequencing costs and times are still falling as new technologies are developed and economies of scale brought to bear. This brings genome sequencing into the cost range of many blood tests, radiological scans, or other investigative procedures and suggests it may soon become a front-line test for many patients with idiopathic disease. Indeed, it may become cheaper for doctors to order a genome sequence than to spend any of their own time wondering about whether to order it.
But genomic data are only useful if someone can interpret them, a far greater task than simply checking for the presence of a mutation in a specific gene. As it happens, each of us carries a couple hundred mutations in our genome that seriously impact on gene function. Most of these do not cause disease, however, and it is therefore a challenge to recognise a pathogenic mutation amongst this background burden of mutations we all carry. That job will be made easier as genetic information becomes available for more and more patients.
A national strategy for genetic services
The enormous potential benefits of such information have been recognised in several countries, most recently in the UK where the NHS has launched a project to sequence 100,000 genomes, including those of thousands of patients with diverse disorders. The genetic heritage of each population is different, however, with some pathogenic mutations at much higher frequencies in specific populations, as with mutations causing cystic fibrosis in Ireland. Characterising the genetic heritage of the Irish population is thus an important goal as a necessary foundation for clinical genetic testing.
The health and economic benefits of this genetic revolution will only be realised if there is adequate provision and funding of genetic testing and genetic counselling services. In Ireland we currently lag far behind most other developed countries in the provision of these services, a situation exacerbated by the recent decision to downgrade what was the National Centre for Medical Genetics at Our Lady’s Hospital in Crumlin to a department within the hospital. On the contrary, if the health service in Ireland is to keep pace with international developments and provide the best care for patients, the role of genetics services will have to be greatly expanded in the future.
[This piece was written for "The Consultant" - the magazine of the Irish Consultants Association and appears in the Spring 2015 issue. It is reproduced here with their consent.]