In My Genes

By getting my exome sequenced, I’m looking for answers but preparing myself for more questions.

By Jeanette McCarthy, MPH, PhD

I am finally getting my genome sequenced! Well, not my whole genome, just my exome, the part made up of genes. Although it represents only a small fraction (less than 2 percent) of my whole genome, this is the part that codes for proteins, and any genetic variation in this region that impacts these proteins may in turn affect my health.

This isn’t my first experience with genetic testing. Through 23andMe, I obtained a less comprehensive survey of genetic variants and learned that I’m a cystic fibrosis mutation carrier. Fortunately, only one copy of this gene is mutated. Had I inherited variants in both copies of this gene, I would have developed cystic fibrosis. I also learned that I inherited a double dose (from both parents) of an HLA variant that predisposes me to autoimmune diseases (fortunately, I have not developed any yet). Because my husband had zero copies of this variant, I am certainly the one responsible for passing the autoimmune variant down to both my kids, contributing to their celiac disease. I didn’t learn much else, though.

With exome sequencing, I’ll be able to find out whether I carry mutations for any of hundreds of rare genetic diseases. I may learn something about my risk of common diseases as well. But what I’m most interested in is finding out which of my genes have “loss of function” variants. These are the ones that may render the gene nonfunctional. In some cases (on average, 20 per person), both copies of a gene may have lost their function, making it all the more intriguing to figure out how I can still be alive and healthy without a functioning copy of that gene.

The fact that I carry this many loss-of-function variants doesn’t bother me. First and foremost, I’m not a worrier — I’ve learned to outsource that. Secondly, genetic variants get a bad rap, especially when you hear them called by their other name, “mutations.” We think about bad diseases when we think about mutations, but I’m wondering how many good mutations I might have as well. We know, for example, that if a person inherits two copies of a mutation in the gene for beta-globin, a component of hemoglobin, he will get sickle cell anemia, but if he inherits only one copy, he is protected against malaria. I imagine there is a mutation that impacts my metabolism, which may have led to my demise in times of famine, but in modern times has allowed me to remain lean. Finally, as we sequence more and more individuals, some genetic variants originally discovered in people with rare diseases and thought to be highly penetrant (a term that denotes the likelihood of getting a disease if one has the variant) are now being found in healthy individuals as well, meaning that these gene variants are not as deterministic as we thought.

But the question I really want to answer is, given my predisposition to autoimmune disorders, why don’t I have celiac disease but my kids do? We shared a similar diet before they went gluten-free. Do I have an undiscovered variant that protects me? Or did the disease require a second variant in a different gene that they got from their father? By sequencing my exome and those of my immediate family, I hope to shed light on this question.

What else might I find? That’s the catch. I have to be prepared to learn about whether I carry variants that predispose me to breast cancer, Alzheimer’s disease, or other disorders. I have to decide if and when I would reveal similar findings to my children should they be found to carry these variants. These are questions that anyone undergoing genome sequencing has to grapple with. I also have to be prepared for uncertainty. Not all of the variants found in my genome will affect my health, but at this early stage of the technology, it’s difficult discriminating the pathogenic from the inconsequential ones.

We think about bad diseases when we think about mutations, but I’m wondering how many good mutations I might have as well.

I’m in an unusual position because I’m a genome scientist, and I know where to get sequencing done. I understand the limitations and ethical/legal/social issues, and I even know how to analyze my own data. I didn’t undertake exome sequencing for diagnostic purposes, but rather to learn firsthand what actual patients might experience and to better understand the questions they might have.

For patients, it’s important to know that professional organizations, like the American College of Medical Genetics (ACMG), are working to address the technical and social/ethical issues related to clinical sequencing. They have produced guidelines to help physicians make decisions about which variants are likely to be pathogenic, as well as how and when to disclose sensitive genetic information. One of the most pressing issues is what to do with incidental findings, which result when you perform a genome sequencing test looking for the cause of one disorder and stumble upon another important, unrelated genetic variant.

I look forward to sharing my insights on personal genome sequencing with the Genome community as I embark on this journey. In the meantime, we’re excited to share related stories in this issue of the magazine. While genome sequencing may be out of reach for most of our readers, a family history serves as an effective proxy for genetic inheritance. Kendall Morgan debunks some myths about family history and describes some new tools for patients to record family history on their home computers and share with their doctors through electronic medical records. In another story, by Turna Ray, you’ll learn about how genetic variation in drug-metabolizing enzymes can contribute to how well a drug works for you — why some patients may require higher doses and others lower doses to achieve a therapeutic effect and avoid side effects. You’ll also find engaging stories about liquid biopsies, designer babies, clinical trials, and more. We hope you enjoy it!