Posted By: The American Journal of Human Genetics, AJHG
Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month, we check in with Kirill to discuss his recent paper, “Low population penetrance of variants associated with inherited retinal degenerations.”
AJHG: What motivated you to start working on this project?
KZ: It was the growing tension between conclusions from controlled lab experiments and the immense variability in inherited disease I encountered during my clinical training. During my PhD, I used gene editing to neatly isolate the effect size of disease-associated genetic variants on neuronal development. During my ophthalmology residency, and especially my fellowship in inherited retinal degenerations (IRDs), which are the leading cause of legal blindness in working adults, I was struck by phenotypic variation among people who shared variants in the same gene. Such variable expressivity seemed at odds with the prevalent assumption that IRDs were mostly monogenic disorders with complete penetrance.
I was fortunate that my mentors at Mass Eye and Ear, Eric Pierce, MD, PhD, and Elizabeth Rossin, MD, PhD, were conceptualizing a project to test whether this assumption held true in large biobanks like NIH All of Us and the UK Biobank. Thanks to support from Foundation Fighting Blindness and the American College of Medical Genetics and Genomics (ACMG) Foundation, I was able work on this project during my fellowship.
AJHG: What about the paper/project most excites you?
KZ: This paper fits into the broader literature suggesting that Mendelian diseases have low population penetrance. The corollary is that there are significantly more people around us who have genotypes that should cause inherited disease than we previously thought. However, as only 10-30% people will manifest disease, the key question becomes: what is special about the 70-90% of people that will not? Is there a general modifying mechanism at play here, or are there as many mechanisms as there are variants? Outside of a few wins, truly personalized medicine, such as gene therapy, appears to be incompatible with the current regulatory and biopharmaceutical market landscape. If there is a general mechanism, there is an opportunity to develop gene-agnostic therapies to help those with inherited retinal disease.
AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?
KZ: The first and most direct is the implication for clinical genetic testing. For presymptomatic individuals without a family history, I believe it should be discouraged due to its low positive predictive value.
Broadly, these findings highlight the importance of comprehensive research into natural human variation at scale. The value of large relational databases that link genetic and phenotypic data, like NIH All of Us and the UK Biobank, in helping address this question is difficult to understate. However, they still capture only a small sample of our population, skewed towards healthier and wealthier participants. There are mountains of data in health records, siloed among physician practices, clinics, hospitals, and labs, all of which use a smorgasbord of electronic health record systems that rarely integrate with one another. Mobilizing this data may be the key to increasing the statistical power necessary to comprehensively detect modifier effects.
AJHG: What advice do you have for trainees/young scientists?
KZ: Your mentors matter. Look for those who show non-zero-sum thinking, who take an active interest in your growth, and invest their time and resources in you. They will be those who are responsive, who engage with your ideas, and who continuously push you. Avoid those who believe the positions of power they occupy are a license to behave as feudal lords and collect tribute. Emulate the former as you advance in your own careers. On this note, I am deeply grateful to exemplary mentors Paul Frankland, PhD and Scellig Stone, MD, PhD, FRCSC, who inspired me to pursue a PhD, to James Ellis, PhD, and Dr. Stephen Scherer, PhD, DSc, FRSC, who gave me space to explore and develop my ideas, and Dr. Eric Pierce and Dr. Elizabeth Rossin, who shaped my thinking on inherited retinal degenerations and merging clinic with research.
AJHG: And for fun, tell us something about your life outside of the lab.
KZ: As I am currently a vitreoretinal surgery fellow, my lab is now the operating room. I do not have much time for a life outside at present, but when I do, I like to spend it hanging out with my 2.5-year-old daughter. They grow up too fast.
Kirill Zaslavsky, MD, PhD, is a Vitreoretinal Surgery Fellow at the University of British Columbia.