Q&A with Heidi Rehm

By Misha Angrist featured image

How did your 14-year-old daughter come to explore her own exome, that is, the sequence of all of her 22,000-plus genes, as a science project last summer?

We were at the orthodontist, and he was knocking with instruments on her tooth, which wouldn’t erupt. Without really knowing my background, he said, “You know, there’s a genetic cause for that.” And then he proceeded to walk over to the computer and type into the PubMed search engine “primary failure of tooth eruption,” and up comes a gene that was implicated in failure of tooth eruption in a nonsyndromic type of clinical disease or whatever. That’s what sparked my interest.

I then talked to a colleague, who said there could be other genes involved. So I said, “Why don’t we just do an exome? We’ll have the orthodontist clinically order it.” My daughter was going to be in my lab for two weeks that summer; she was in ninth-grade biology, learning about genetics. I thought she could participate in the analysis and look for variants in those genes. I thought it would be a good summer project. In the end, we didn’t find any genetic cause, and her tooth finally erupted.

Instead, of course, we found an incidental finding, which became the subject of further pursuit.

And, as you told STAT last year, it wasn’t just any incidental finding. It was a variant in the MYH7 gene associated with dilated cardiomyopathy (DCM) — an enlargement of the heart — that you happen to know a fair bit about because you’ve studied it extensively. It can lead to sudden death.

The genetics fellow in my lab called me that night and said, “[We found] a DCM variant that was reported as ‘likely pathogenic.’” (Editor’s note: “Pathogenic” means “disease-causing.”) My question was, “What lab reported it?” And she was like, “Our lab.” I said, “Oh, okay, I guess I should take this more seriously.”

You found five other cardiomyopathy patients with this same DNA variant in the literature, and you contacted other genetics labs that do cardiomyopathy testing and found a few more patients on top of that. And yet this variant was not found in healthy controls.

Right. All of the data really pointed to this being a pathogenic DCM variant.

What did you do at that point?

I had to think about my family history. I had had my own genome sequenced through the Personal Genome Project, so I could just go online and immediately see that that variant was in my genome. And then I collected saliva samples from my parents and found that my mother was positive for it, too.

Meanwhile, within a couple of days, I went in for an echocardiogram and an electrocardiogram (EKG). And as it happened, my mother had had [her own cardio workup] six months earlier at age 75; both of our hearts were normal. I have no family history of any cardiac disease or anything suspicious for sudden cardiac death or anything like that.

[Because of that], I didn’t feel that my daughter was imminently at risk. But at the same time, I was well versed in the fact that cardiomyopathy can manifest in one individual at a very different age from another individual. The fact that my mother and I don’t have disease doesn’t mean my daughter has no chance of developing disease before adulthood. What weighed on my mind were two things. One, she’s young — do I want this in her medical record? And two, the possibility of her facing discrimination in life and/or long-term disability insurance. (Editor’s note: The Genetic Information Nondiscrimination Act protects against genetic discrimination in health insurance and employment, but does not cover life, long-term care, or disability insurance.)

Ultimately I decided that this information is clinically important. And if it’s clinically important, then it should be in her medical record. It’ll likely be something where she’ll get [a cardiac evaluation] in high school this summer and again in college — and from there, maybe once every five years or something.

You started out thinking you were going to have your daughter spend a couple of weeks in your lab learning some genetics by studying fairly innocuous variants in dental genes, but you wound up falling down a much different and potentially much scarier rabbit hole. Do you have any regrets?

It’s certainly been educational for my daughter, and I think knowing this information puts us in a position to take seriously any symptoms that may develop in the future and not ignore, say, chest pain or shortness of breath. I think I’d rather be informed and understand my risks and take appropriate actions than not be aware of [those risks]. So I think it was the right decision.

Why did you decide to talk about it publicly?

First I should say that I got consent from my daughter and my mother [before I started speaking about it publicly]. Second, my view is that it’s a great teaching example of the importance of sharing detailed clinical information. And by putting this specific variant out there, it’s possible we’ll find other individuals around the world who also have it. The more we can collect full genomic data sets on everyone with this variant, then maybe we can start to understand why I might or might not be at risk but others are [or aren’t]. I see it as a platform to advance an agenda that I think is in the best interests of both the broader population and those of my daughter, my mother, and myself.