Patients in Waiting


The 10 high-profile volunteers currently having their genomes sequenced as part of the Personal Genome Project.

When people learn that I have been sequenced as part of George Church’s Personal Genome Project (PGP) they often say, “Wow- I’d like to be sequenced too!” My first response to them is, “Why – are you sick?” If the last decade has taught us anything, it’s that sequencing healthy people returns mainly raised eyebrows, but little more. Sequencing cancer patients and their tumors, on the other hand, can be life saving. Dr. Lukas Wartman probably saved himself from an early cancer death by being sequenced.

Genomic sequencing of children with unexplained illnesses also leads to heartwarming breakthroughs. The Beery brother and sister pair, Noah and Alexis, had severe dystonia from birth and could barely breathe or walk. Misdiagnosed and mistreated as having cerebral palsy, the medical and emotional cost of this failed diagnosis on the Beery family was huge.  Genomic sequencing revealed that they were complex heterozygotes for null mutations in the gene sepiapterin reductase, causing a known dopamine-linked dystonia that can be rescued by dietary supplementation. Properly treated, they now lead normal, healthy lives. Other similar pediatric miracles, such as solving a case of inflammatory bowel disease, come to mind.

The Beery Family

The Beery Family

Sequencing normal healthy people, in my experience, just tends to undermine the confidence one has in peer reviewed medical literature. I was on hand in Boston in 2008 when the first 10 completed sequences of the Personal Genome Project were rolled out. I had a special vested interest, in that mine was genome number 5. When the sequences were reported, we were all taken individually and counseled about a few of our “calls.” Remember – almost any genome will have something like 3 million SNP variants that differ with respect to the reference genome. So to say this was cherry picking, or barely skimming the surface, would both be understatements. Then they brought us back together to discuss the impact this had on us. John Halamka (PGP-2) was standing there looking sheepish because he was supposed to have an autosomal dominant neuropathy…but he didn’t. When I looked at my own data, I found mostly very vague GWAS associations. What does it really mean if you have a single nucleotide variant that is within an intron in a gene of unknown function, and that a GWAS study found it is associated with a 2.8% increase in the chance of rheumatoid arthritis, which I don’t have? Four of the first PGP-10 volunteers had mutations in the gene ELAC2 on chromosome 17, supposedly linked to prostate cancer. I was one of those – but I have a low PSA value and no history of any relative having prostate cancer for 4 generations. Fully 70% of the PGP-10 had mutations in the SP110 gene supposedly making us more susceptible to tuberculosis. Hmm. Lots of raised eyebrows and shrugged shoulders.

Looking deeper, I came across my KCNQ3 gene. The KCNQ genes are a family of voltage gated potassium channels, now numbering 1-5, working as heteromers with each other to generate the neuronal M-type current. I happen to have a single nucleotide mutation in one copy of KCNQ3, converting Arginine 777 to Glutamine. Scanning the literature, I found six other known human KCNQ3 mutants – Trp309Arg, Pro574Ser, Ala381Val, R330Cys, Gly311Val and Gly263Val – but not mine. All these other mutations lead to epileptic seizures, mostly BFNC or Benign Familial Neonatal Convulsions. They act as autosomal dominants, so only one bad copy of KCNQ3 is needed in order to have the seizure disorder. The only problem for me is…I’ve never had a seizure. What I’ve become is a “Patient in Waiting.” Otherwise called a hypochondriac made-to-order by too much genomic sequencing, or a person who is now startled by their smallest involuntary twitch.

The number of patients in waiting grows daily, as more humans are sequenced and more mutations are called…in healthy people who don’t have what the mutation is supposed to predict. I’ve included in this post the story of another such patient, a little girl named Laura Inestroza. Her story, and the fact that despite her genome, she does not have cystic fibrosis, were recently reported in The Wall Street Journal. So Laura, here’s to you, and to me, and to a long and healthy life for all of us who are proving that genes, for all that we know about them, are still keeping a lot of secrets.

Laura Inestroza, 4, was found at birth to have the genetic changes associated with cystic fibrosis, but she still has no symptoms. Michal Czerwonka for The Wall Street Journal By Amy Dockser Marcus

Laura Inestroza, 4, was found at birth to have the genetic changes associated with cystic fibrosis, but she still has no symptoms. Michal Czerwonka for The Wall Street Journal By Amy Dockser Marcus

To read the full WSJ article, Genetic Testing Leaves More Patients Living in Limbo, click here.

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1 Response to Patients in Waiting

  1. Pingback: Phenotyping and the Bucketmouth Beard | Kirk M. Maxey: Blog and Website

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