Should little Ari get his whole genome sequenced?
Of the hundreds of messages that Vy and I received after we published a long post last week about our son Ari, who was born on December 23 with various developmental delays and signs of a potentially serious congenital condition, some of the most salient feedback came from readers who wanted to comment on the role of medical diagnostics, including whole genome sequencing (WGS), in helping to resolve the gnawing uncertainties about Ari’s health status.
Overall, feedback on the value of WGS at this stage was mixed. A few people, including several experienced clinicians, told us that it was unlikely to reveal much, and that we should focus on providing the day-to-day care that will help him thrive in this initial and critical stage of his life, irrespective of whatever numbers are printed on his genetic lottery ticket. Others argued that taking a more stepwise approach to diagnosis could cause us to miss a window where early action would make a difference, especially if he turns out to have a condition that can be reversed with relatively simple interventions.
Vy and I still haven’t decided on which approach makes the most sense, but here’s a bit more on where we are right now and what we know so far.
To recap a bit of the background, the worries all started when our neonatal pediatrician expressed concerns that Ari was unusually small and weak for a full-term newborn. More ominously, he noted that our son has some of the markers of Prader-Willi Syndrome (PWS), a major developmental disability that has huge implications for his long-term health and ability to live independently. He referred us to a pediatric neurologist, who advised us to re-admit our son to the NICU at Mount Elizabeth Hospital for medical investigation and intervention, including insertion of a nasogastric tube to ensure that he can feed properly.
After three days and two nights in the NICU, the pediatric neurologist agreed that our son may have an underlying condition that could explain his multiple developmental issues. She brought in a speech pathologist to assess his weak feeding reflexes. She also ordered tests for three specific diseases, including myasthenia gravis, a potential autoimmune disease in the mother that could have silently impacted the pregnancy, as well as for PWS and myotonic dystrophy, two congenital conditions that can be detected via tests that are available at local labs in Singapore.
During that period, the pediatric neurologist also told us about WGS testing. She noted that this option was expensive, required blood samples from the parents as well as the newborn, would only be helpful for identifying some of the rarer genetic conditions, and would typically come later in the diagnostic process. She also explained the risk of “incidental findings,” or discoveries during the WGS analysis that are unrelated to Ari’s specific issues and could raise entirely new medical concerns for the three of us.
I personally wasn’t fazed by the idea of incidental findings — if anything, I was intrigued by what other secrets lay buried in my genetic code, and even asked if I could get a copy of my sequence to keep for myself (answer: maybe). The cost was still a concern, but Vy and I initially made a snap decision to go for WGS right away, as our reflex was to throw the kitchen sink at the problem and cover all bases. We signed all the forms and went to the lab for blood collection, at which point the samples were speedily couriered to PreventionGenetics, a genetic analysis company in the United States.
The following day, however, we faced some serious buyer’s remorse when the total bill for the testing services came out to roughly USD $10,000 (SGD $13,000) — more than double what we expected when we first agreed to the tests. Fortunately, our pediatric neurologist understood how and why the misunderstanding arose and took rapid steps to rectify the situation. She quickly contacted PreventionGenetics, which agreed provisionally to bank the blood until some of the more routine tests come back and we have a better idea about next steps.
With the problem temporarily resolved and our second NICU visit soon behind us, the situation improved after we brought our son home. The nasogastric tube feeding was a drag, but it helped him grow and gain energy, and the home environment allowed us to give him a lot more interpersonal stimulation, fresh air and natural light than he got at the hospital. By day 11, he finally made it back up to his birth weight of 2.35 kg (5.18 lbs). He was still very small and weak, and still didn’t cry like a normal baby, but he gradually got more comfortable with bottle feeding. He rarely drank more than 10ml at a time, but at least we were moving in the right direction.
On Jan 5, we went back to the hospital for a follow up with the pediatric neurologist. She informed us that the test for myasthenia gravis came back negative, and that we are still waiting for the results from the two congenital tests, which are currently being processed at the lab at KK Women’s and Children’s Hospital in Singapore. Given Ari’s growth and level of physical activity, she told us that PWS was starting to look a little less likely, but we wouldn’t know for sure in the absence of a lab test.
If Ari tested negative for both PWS and myotonic dystrophy, the next step would be to order a comprehensive panel of tests for various neuromuscular disorders with a company called Invitae and for a cost of USD $250 (SGD $340). Since we already had blood samples ready to go with PreventionGenetics, we could also consider casting a wider net and going for WGS right away, but given that it costs 20–40x more than the neuromuscular panel and would only expand our likelihood of achieving a diagnosis by roughly 20%, the right choice was not clearly evident.
For now, we have decided to wait on WGS, especially since other options may arise. After reading our story, for example, a local biotech firm in Singapore reached out and offered to conduct the WGS for free, and then send the data over to their partners at a leading US academic medical center for clinical annotation. Due to local regulations, however, Singapore clinicians are only allowed to interpret and apply the results if they are generated at a lab that meets certain accreditation standards, and no labs in Singapore meet the necessary requirements.
Whatever approach we take, Vy and I are mindful that a clear and definitive diagnosis may not necessarily make a difference in how we care for our son. It might even be counterproductive if it leads us to pathologize a set of attributes that currently look like developmental delays but which could actually be immaterial or perhaps even adaptive in the long term. In other words, we are mindful of iatrogenic risks and the fallacy of genetic determinism.
Still, if we are indeed facing a serious health issue, we want to know soon so that we can give him the right support and seek out early interventions that could make his life better, so the decision of when and how to include WGS in our care plan is a tough one. If you were us, what would you do?
