Kirsty and Aaron McConnell spent 16 months watching their baby daughter Lily slowly lose her ability to move, eat, sleep, and eventually breathe.
There was nothing the couple could do to prevent the cruel march of spinal muscular atrophy (SMA) type 1, which finally and predictably claimed their daughter’s life in March this year.
“It completely devastated our family,” Ms McConnell told The Medical Republic.
“It was an incredibly difficult and horrific condition. I basically had to watch her muscles slowly waste away every day.”
Neither Ms McConnell, nor her husband, had a family history of SMA. Both had healthy children through previous relationships.
But, unbeknown to the couple, they were each carriers of a recessive gene for SMA, which gave their offspring a one in four chance of being afflicted. Screening for SMA was not raised as a possibility at any point before or during pregnancy, Ms McConnell said.
“Personally, I’m a list-ticker,” she said. “When Aaron and I got married we knew that we wanted to have a child together so [genetic carrier screening] would have been on my to-do list for preparing for pregnancy and it just wasn’t offered. There was no knowledge about it.”
The odds of having a baby with SMA are extremely low, with only around one in every 10,000 births affected. But SMA and related syndromes still cause around 630 deaths every year in Australia.
There was a common misconception among health professionals that people were only at risk of carrying the SMA gene if they had a family history of the condition, said Alison Archibald, an associate genetic counsellor with Victorian Clinical Genetics Services (VCGS).
In reality, the SMA gene is fairly common, with around one in every 40 being a carrier.
Other genetic conditions with a relatively high carrier frequency include cystic fibrosis and fragile X syndrome, with rates of 1 in 25 and 1 in 250, respectively.
A recent study of 12,000 individuals in Victoria conducted by the Murdoch Children’s Research Institute and VCGS found that one in every 240 couples was at high risk of having a child with SMA, cystic fibrosis, or fragile X syndrome.1
“What we’ve shown is that although individually these conditions are considered rare, collectively it is actually relatively common to be a carrier for at least one,” Ms Archibald, the lead author on the paper, said.
Of these, around one in 1000 pregnant women who were identified as carriers for one of the three conditions had an affected pregnancy.
The researchers argue these numbers provide a strong rationale for population carrier screening.
The NSW government has taken a similar positon. The Minister for Health, Brad Hazzard, recently sent a letter to GPs asking them to inform people of the availability of pre-pregnancy genetic carrier screening. NSW Health is currently revising the “Thinking of Having a Baby” brochure to reflect this view.
However, charging full steam ahead with genetic screening in general practice raises some pretty significant issues.
One conspicuous problem was that GPs were not trained to offer pre-test genetic counselling, Dr Linda Mann, a GP in Leichhardt, NSW, said.
“To lay on general practice the responsibility for essentially population screening for these conditions is a joke at the current level of understanding for those GPs,” she said.
Training for GP registrars in NSW includes a single one-hour lecture on genetics, which Dr Mann delivers as part of GP Synergy.
“I look forward to the Minister’s, or RANZCOG’s, or RACP’s, or RACGP’s funded GP education program, especially for the majority of us over 40, who have limited exposure to … all the new considerations in the genomic world,” she said.
A genetics resource for GPs including a section on genetic carrier screening is due to be published next year, with the support of the RACGP.
But there is currently no easily accessible information on genetic carrier screening on the NSW Centre for Genetics Education website, which is the usual go-to resource for GPs in this state.
“If you want me to be a genetically knowledgeable GP you need to make accessible genetic resources,” Dr Mann said. “Are genetic resources available? They are not.”
Exacerbating the difficulty, consultations about genetic screening were too time-consuming to squeeze into antenatal visits, she said.
“First antenatal visits are already 30 minutes long while I collect the relevant family history, do my pre-test HIV counselling, discuss the timing of NIPT and the relevance of pre-eclampsia screening,” Dr Mann said. “To adequately explain the nuance of a variable characteristic like screening for fragile X syndrome is just a step too far. Sorry.”
Referral was hopeless too, Dr Mann said. “I know the local genetic referral agency has a 15-month wait, and advises me to use Westmead. This is central Sydney. Imagine what this is like if you’re in [the regional NSW town of] Bathurst?”
But it was not acceptable for GPs to say it was all too hard, Dr Jonathan Cohen, a GP and the medical director at Genetic Clinics Australia, said.
“For a doctor nowadays, in 2017, to say, ‘I’m not going to tell people about [genetic carrier screening]’, I think is abrogating their duty of care,” he said.
Waiting times were a real problem, he acknowledged, but genetic counsellors were available at every public-health facility over the phone. “And if it is urgent, if someone is pregnant and they need to be tested, they will get into a public facility within two days.”
Probably the biggest issue was with GPs’ perceived lack of education about genetics, Dr Cohen said.
“Like all things in medicine, GPs do need to continue to self-educate,” he said. “Just type in the name of any genetic condition online and you will be flooded with information from reliable medical sources.”
The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) remains on the fence about whether screening should be routinely offered by GPs.
Adding another test might sound like best practice, but “in reality we just have to be sure if it is offered that it is done in an appropriate and responsible way”, Associate Professor Lisa Hui, an academic obstetrician and gynaecologist at the University of Melbourne, and a spokesperson for RANZCOG, said.
From a public-health perspective, Down syndrome and other chromosome conditions (including Edwards syndrome and Patau syndrome) remained a higher priority for now because they were more common, she said.
While genetic screening was a relatively straightforward test to order, the counselling required prior to ordering the tests was complicated, Dr William Milford, an obstetrician and gynaecologist, said.
The GP would need to have a five to 10-minute discussion with the patient covering the following topics:
•What are the diseases that are being screened for?
• How often they occur
• The likelihood of the patient being a carrier
• The chances of having a child with a genetic condition if both partners are carriers
• Whether to test the carrier status of the woman first or the woman and man at the same time
• The available options if both partners are found to be carriers, including: IVF and pre-implantation genetic diagnosis; or natural conception, prenatal diagnosis and possible termination
• The residual risk of having a child with a genetic condition after receiving a negative result
• The cost of the test
Detailed information about the characteristics of each genetic disease could be highly relevant to a patient’s decision about whether to be screened or not, Dr Milford said.
While severity of a condition cannot be predicted, the vast majority of people with SMA, fragile X syndrome and cystic fibrosis are, or will be, significantly to severely affected.
Some genetic conditions, such as SMA type 1, are fatal early in childhood and result in a poor quality of life. Other conditions, such as cystic fibrosis, are not immediately life-threatening.
The expression of the fragile X gene is also somewhat variable, although the majority of people have moderate to severe learning and behavioural problems.
An additional complexity is that screening for fragile X can be relevant for the health of permutation carriers themselves, as they are at heightened risk of fragile X-associated tremor/ataxi syndrome or premature ovarian failure.
“[All this] makes counselling complicated and difficult and also makes any decision-making by the family fairly fraught,” Dr Milford said.
The tests are not cheap either, which can influence a patient’s decision. The genetic carrier screening offered by VCGS does not attract a Medicare rebate and has an out-of-pocket cost of about $385.
Genetic carrier screening is highly accurate; the detection rate of carrier tests for cystic fibrosis, fragile X syndrome and SMA ranges from 95% to over 99%. However, the reality was that some cases of genetic disease would not be prevented by screening, Sarah Long, a genetic counsellor at Genetic Services of Western Australia, said.
It was important that patients understood this, particularly those undertaking expanded carrier screening, she said.
Otherwise, parents could be under the impression that there was zero chance of their child having certain genetic diseases, which could lead to problems with diagnosis, or incite litigation, in the event of a false negative.
A number of IVF clinics, as well as Genetic Clinics Australia, are currently offering the Counsyl Foresight carrier screen for 175 genetic conditions.
Dr Cohen said his clinic discussed the reliability of the test in counselling and that there was more information online.
“Part of counselling for screening is to discuss with patients that fact that it is not possible to cover everything known and unknown,” he said. “Most understand this.”
While it was reasonable for people to want to lower their risk of passing on a genetic disorder, it was very important for GPs to adjust patient expectations, Ms Long said.
All individuals carry at least three clinically severe recessive childood disorders, out of a possible 7000, but even expanded genetic screening only tests for a fraction of these.
“About 3% to 4% of babies have a birth defect or a condition when they are born, and no matter how much testing you do, you are probably not going to reduce that by very much,” Ms Long said.
Making patients aware of genetic screening could just be a matter of handing a patient a two-page fact sheet and then getting them back to answer questions, Dr Milford suggested.
But, at the moment, all the education materials are being created by commercially interested groups, which is a source of “mild discomfort” for Dr Milford. “If someone has a vested interest then the information is going to be biased such that it is going to push people towards doing the test,” he said. “The information needs to be provided in a completely unbiased fashion.”
The Murdoch Children’s Research Institute was recently criticised for drawing an erroneous comparison between the rates of Down syndrome and the combined rates of cystic fibrosis, fragile X syndrome and SMA.2
While the combined rate of CF/SMA/FXS among women identified as carriers was around 1 in 1000 pregnancies in this study, this was not similar to the rate of pregnancies affected by Down syndrome as the authors suggested. The most recent published data from Victoria showed the actual rate of Down syndrome in 2015 was one in 360 pregnancies.
Down Syndrome was extremely difficult to attribute one figure because the rate decreased during pregnancy due to miscarriages and terminations, a spokesperson for MCRI said. “We have simply chosen different ways of presenting the data.”
Their paper relied on a statistic for Down syndrome live births from 1983, even though there are more up-to-date figures in the literature.
The media release also incorrectly portrayed SMA as the “biggest killer” of babies under two years in Australia, when SMA was, in fact, the leading cause of death only among genetic diseases.3
The researchers were employees of VCGS, which is a not-for-profit provider of a range of genetic tests, including the “Prepair” genetic carrier screening test.
The researchers defended their interpretation of the facts, but the disagreement demonstrates the variety of opinion, and perhaps the need for greater independence to dispel suspicions of bias.
This is not the first time that general practitioners have been asked to wear the genetic counsellor’s hat.
Over the past four years, GPs have started ordering non-invasive prenatal testing (NIPT) for Down syndrome. NIPT is an increasingly popular alternative to combined first trimester screening. It costs around $500 and is not Medicare funded.
Many GPs were not sufficiently trained to offer high quality genetic counselling to accompany the NIPT, Dr Milford said.
There was still widespread misunderstanding about how to manage positive and negative results, he said. A common mistake by health professionals and patients was failing to recognise that NIPT was not a diagnostic test, and that amniocentesis or chorionic villus sampling (CVS) needed to be performed to confirm the result.
NIPT also screened for rarer chromosomal conditions, such as Prader-Willi syndrome and Angelman syndrome. These syndromes were less-severe conditions that affect babies and children variably. “And so, the decision-making about what you do if you have a positive test result in this regard is quite complicated. You need quite structured counselling,” Dr Milford said.
A routine GP appointment was not long enough to cover these points in detail, Ms Long said.
“How are GPs meant to counsel with all this information they have to get through?” she said. “It is unfair to put that expectation on them but I don’t really have an answer about how better to do that at the moment.”
Professor Nigel Laing, who heads the laboratory for neurogenetic disease at the Harry Perkins Institute of Medical Research, believes Australia may find those answers overseas.
The Netherlands has been running pilot programs for genetic screening in general practice and Israel has been offering genetic screening for nearly 100 recessive conditions to its entire population, free of charge, since 2013.
The Israelis are currently screening more than 60,000 people per year out of a population of around 8.1 million.4 The program tests each ethnic group separately for all severe diseases with a carrier frequency of 1:60 (or a frequency of one in 15,000 live births).
“They are much better organised than we are,” Professor Laing said. Unless Australia worked on delivering infrastructure to support genetic screening, couples would continue to play “genetic roulette”, he said.
But for those affected by the traumatic reality of a childhood genetic disease, change cannot come soon enough.
“Just give people choice,” Ms McConnell said. “Because what we went through, I wouldn’t wish it upon anyone.”