The TGMI are committed to making the benefits of genetic testing more widely available. One of the key ways of achieving this is by making genetic testing accessible through routine medical appointments. This is sometimes termed ‘mainstreaming’.
Deciding how, and in whom, we should mainstream genetic testing is complex, requiring consideration of many scientific, medical, logistical and financial factors.
This week my research group published a paper that suggests mainstreaming genetic testing in children with overgrowth and intellectual disability (OGID) could be useful and successful.
Genetic testing in OGID is currently very restricted
Overgrowth syndromes are a nebulous group of conditions defined as having increased height and/or head circumference compared to children of the same age, together with other medical problems, the most common of which is intellectual disability. We have introduced the short-term ‘OGID’ to describe children with both increased growth and intellectual disability.
My team has been studying this group of conditions for a decade and have identified several genes that cause OGID when their functions are altered by a mutation. As each new OGID gene was discovered an individual test for it was also developed. Because DNA sequencing technology was a small-scale and very expensive process, a lot of effort was expended in trying to decide which children should have gene testing. Typically the child was reviewed by a clinical geneticist who would do a very detailed review of their medical history, a comprehensive physical examination, sometimes order X-Rays or other tests and would then use the information to decide if the child was likely to have a mutation in an OGID gene. If it was deemed likely a test for that specific gene was ordered.
Newer gene testing methods can increase testing access
Fast, affordable, large-scale DNA sequencing is changing how and at what point in the patient pathway gene testing can be used. Instead of using time and expertise to decide who should have a test we now have the option of doing upfront testing in more people and then spending our time and expertise using the test results to optimise management. But we still can’t just test anyone. Even if the cost of DNA sequencing becomes pennies a genetic test also involves analysis and interpretation of the data and the real cost will remain hundreds of pounds, for the foreseeable future. So we still have to make choices about who to test. How we make those choices depends on the condition, the test, and who will be ordering the test.
Mainstreaming only works if testing criteria are simple
For mainstream genetic testing to be successful the test eligibility criteria have to be simple to implement and remember. This is because mainstreaming is explicitly about non-specialists ordering the genetic test. These non-specialists may be from diverse medical disciplines and genetics will not be their primary area of interest or expertise. The genetic test will be one component of their work, probably a very, very small one. If each test requires them to look-up and apply complex eligibility criteria it acts as a strong deterrent to testing and mainstreaming will fail.
We have been one of the pioneers of mainstream BRCA gene testing in women with ovarian cancer. Traditionally, ordering a BRCA test involved very complex family history evaluations to decide who to test. The complexity and reliance on family information acted as a deterrent, even within genetics! In turn, this has led to inconsistent BRCA testing, in every healthcare system. Usually the blame for the patchy deployment of BRCA testing has been placed on the inability of healthcare professionals to take family histories adequately! Many papers have been written about this over the last 20 years, and many efforts to make people better at systematically taking family histories have been tried. All have failed (to my knowledge).
Under our noses was a much better solution – to make the testing criteria simpler. Most countries have a stated aim to offer BRCA testing to people with a 10% chance of having a mutation. Using family history information is one way of determining that. But in fact any women with ovarian cancer is at >10% chance of having a mutation.
This is an ideal test eligibility criterion for mainstreaming. Anyone can remember ‘every woman with ovarian cancer is eligible for genetic testing’. Patient, specialist, non-specialist, anyone can understand and remember this. Furthermore, implementing the criteria requires using information that is already available. No additional work is needed. Having this single simple testing eligibility criterion, based on known information, was the primary reason BRCA testing has been successfully mainstreamed; in our institution most BRCA tests are now ordered by non-geneticists. There are, of course, many other issues that have to be addressed for a mainstreamed genetic test to work (see our papers and website for more details). But without simple testing criteria it cannot work.
OGID is ideally suited to mainstreaming genetic testing
In our new OGID study we undertook exome sequencing in children who had a height or head circumference at least 2 standard deviations above the mean and who also had an intellectual disability. These growth measurements are routinely and easily measured when a child is referred to a doctor. The intellectual disability was simply classified as mild / moderate / severe / unspecified and was designated at the referrer’s discretion.So the eligibility criteria were simple, did not require specialist knowledge to implement, and relied on information that was already available. We included 710 children in the study, recruited by 100s of different clinicians.
We found that 50% of the children in our study, who had been included because they fulfilled these simple, non-specialist criteria, had a disease-causing mutation in one of 14 different genes. This is an excellent diagnostic yield. It is much higher than many other conditions where much stricter and more complex criteria are used to improve the test success rate. There are various reasons why this might be, which we discuss briefly in the paper (the study is about exploring the genetic architecture and molecular pathways involved in human growth control – its relevance to mainstreaming was an unanticipated bonus outcome!)
It would be straightforward to use these two simple criteria in a non-specialist, general paediatric clinic setting to decide which children can be offered genetic testing. I hope that many centres will try it. I suspect the diagnostic yield will be a little lower than in our study (for various reasons), but I believe it will be high enough to make mainstreaming genetic testing in OGID practical, useful and cost-effective.
I also believe there will, increasingly, be other conditions where we can start to make genetic testing an early, routine part of medical care.