Thursday, March 6, 2014

Blogging My Genome, episode 2: scratching the surface

After learning about Illumina's Understand Your Genome (UYG) program at ASHG 2013, I decided to sign up to get my genome sequenced. This is the second in a series of blog posts I'll write about my own adventure in very personal genomics!

Three months after shipping my blood sample off to the lab for whole-genome sequencing (WGS), I got the long-awaited message to come in and go over my results. And so on a rainy Friday afternoon I biked over to Stanford for genetic counseling. I was very excited, and yet not without awareness of the ~1% chance I could see one of the known pathogenic findings on the American College of Medical Genetics list for genome sequencing reports, and perhaps up to ~5% chance of some other medically actionable finding.

Fortunately, nothing like that came up. In fact, my report is quite unremarkable, which is of course a good thing:

In this context, a variant refers to the DNA sequence at a specific position in my genome, where my sequence differs from the human reference genome assembly, or the sequence at that position is known to vary across humans, or both. As the report says, Illumina curated 5,390 of my variants using a combination of automatic filtration by algorithms and manual study by a medical geneticist - resulting in this report with just four variants. The report goes on to detail the rationale for highlighting each of these, with references to relevant research papers and allele frequencies from the 1000 Genomes project.

Nothing in my report is really of great concern, as virtually everyone would have a couple variants of unknown significance (VUS) as well as potential carrier status for some rare genetic diseases. My one "clinically significant" and "suspicious" VUS in MYOC was flagged as such because (1) other mutations in that gene are known to cause a type of glaucoma, (2) the particular missense variant I have has been seen in a couple glaucoma studies on people of Chinese descent, although not with any statistically credible enrichment, and (3) its allele frequency from 1000 Genomes is around 0.5%, meaning it is rare and "consistent with disease prevalence." Overall, this is interesting but pretty thin - for now it suggests I ought to continue getting annual eye exams, as I have been, and that's about it.

But wait - there's more!

Now before I take my clean bill of genomic health down the street to California Cryobank and demand a pay raise, the report has some notable fine print:

1,600 genes is well under 10% of the known genes in the human genome. Moreover, Illumina has only interpreted single-nucleotide variants in the exons of those genes, which are typically just a few percent of the DNA therein. It really just scratches the surface!

It's perfectly understandable and appropriate that the interpretation covers so "little" - though of course it does cover an awful lot - because geneticists' understanding of how to medically interpret the many other kinds of variation is, by and large, just not good enough for responsible diagnostic testing. That's especially true in the absence of any actual symptoms to inform the interpretation. On the other hand, it seems difficult to escape the conclusion that this clinical WGS report doesn't add very much compared to less-expensive exome sequencing.

So, was my $5,000 poorly spent? It bought peace of mind to a certain degree, of course. But more importantly it bought this:

That is- not only the interpretation report, but also the underlying raw data. In the next episode, I'll start to dig in to the goodies here!