Posted By: Sara Cullinan, PhD, Deputy Editor, 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 Garry Cutting, to discuss ‘Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity.’
AJHG: What prompted you to start working on this project?
Garry: This project is part of an ongoing effort to interpret the molecular consequences of all variants in the CFTR gene. The variants selected for this study are associated with a wide-range of disease severity, allowing us to determine the utility of functional assays for variants that associate with moderate to mild forms of disease.
AJHG: What about this paper project most excites you?
Garry: We were surprised to find that a number of the putative disease-causing missense variants had minimal effect on protein function and that predictive algorithms have difficulty interpreting these “minimal effect” variants. Conversely, it was reassuring to find that incorporation of functional data improves annotation using expert and ACMG/AMP criteria.
AJHG: Thinking about the bigger picture, what implications do you see from this work for the large human genetics community?
Garry: Missense variants are challenging to interpret and many are labeled as variants of unknown significance. Our study indicates that classifying missense variants, especially those associated with intermediate severity of disease, will require functional testing in the appropriate context. Our work also shows that current predictive algorithms should be used with caution as they tend to overcall missense variants as deleterious.
AJHG: What advice do you have for trainees/young scientists?
Garry: The explosion of DNA variant information provides a wonderful opportunity to investigate their effect upon RNA transcription, RNA splicing, protein stability, and protein function. Individuals who become facile with these techniques will be highly valued as we move from DNA sequencing to variant annotation and elucidation of disease mechanism.
AJHG: Tell us something about your life outside the lab.
Garry: I really enjoy working with my hands to repair something broken or build something new. Unlike the long time frames that we experience in science, fixing something can produce results in a much shorter time frame. Sometimes things go wrong, but you always seem to learn something new when you undertake projects that are out of your established area of expertise. Consequently, I fully agree that circuit breakers and water supply values should be turned off before undertaking home projects.
Garry Cutting, MD, is an Aetna/U.S. Healthcare Professor of Medical Genetics at John Hopkins. He has been a member of ASHG since 1997.