I recently had a series of moderately unpleasant health problems, which eventually led to my being tested for a rare, and potentially very serious, genetic disease (for worried parties: the test was negative). I thought I would share this anecdote because, first, it’s the only time I’ve wished I had more genetic information about myself in a medical setting, and second, because it illustrates the sorts of gaps in medical knowledge that could be aided by routine genome sequencing.
I presented, as they say, with palpitations and syncope: briefly, while standing at a church during a wedding, I had passed out, and for a couple weeks since had been experiencing a host of unpleasant symptoms, including heart palpitations, chest pain, lightheadedness, and general fatigue. After a couple of chats with my GP, I was referred to a cardiologist.
The cardiologist reported that I had a somewhat abnormal EKG pattern, consistent with Brugada syndrome, an autosomal dominant genetic disease most notable (to me) for the fact that its primary symptom is sudden cardiac death. However, the particular EKG pattern I had was not diagnostic, and indeed is sometimes reported as a normal variant .
I agreed that it seemed reasonable to do a more diagnostic test. The cardiologist explained the possibilities to me, one of which entailed something along the lines of inserting electrodes through a vein directly into my heart. I, of course, asked why he couldn’t just sequence the bloody gene.
As it turns out, it’s not quite that simple— the test, if done commercially, costs over five thousand dollars (I’m ashamed to admit I hadn’t really totally realized how absurd prices for genetic testing are until I looked that up), but more importantly, mutations in the known causal genes can be found in only something like 30% of patients with the syndrome. Still, readers here can probably appreciate how frustrating it was to be unable to check immediately for these mutations.
In any case, I agreed to plan for a non-invasive test for the disease, and spent the next week scouring the literature and furiously calculating posterior probabilities: probability of Brugada syndrome given my symptoms, lack of family history, and the EKG; probability of sudden death given Brugada and the EKG; etc. By any reasonable calculation, these probabilities were all small but non-negligible.
In the end, the test was negative.
This whole episode was somewhat stressful and surreal, but it got me thinking a bit about the role of genome sequencing in medicine. What’s really striking to me is that the price of whole genome sequencing is already competitive with commercial Sanger sequencing tests of individual genes. As I mentioned, 70% of Brugada syndome cases cannot be linked to any individual gene. If instead of the commercial tests, these 70% of patients had their entire genomes sequenced, I bet the number of known causal genes would go up considerably. And my guess is that patients with mutations in different genes have somewhat different prognoses, and could be stratified by risk to some extent. People have talked about the role of sequencing in medicine for years; I hadn’t realized this was feasible (and economical) right now.
 For those familiar with the syndrome, my EKG is type III Brugada pattern (see the image in the post). Wikipedia says “Type 3 pattern is not uncommon in healthy subjects”, but the best estimates I could find in the literature put its prevalence at ~0.5%, which isn’t exactly common either.