Trainee Author: Dr. Callie Kwartler
Milewicz Lab – University of Texas Health Science Center at Houston
(Photo courtesy Kwartler)
Kwartler CS, Gong L, Chen J, Wang S, Kulmacz R, Duan XY, Janda A, Huang J, Kamm KE, Stull JT, Guo D, Milewicz DM. Variants of Unknown Significance in Genes Associated with Heritable Thoracic Aortic Disease Can Be Low Penetrant “Risk Variants”. Am J Hum Genet. 2018 Jul 5;103(1):138-143.
Kwartler et al. (2018) set out to determine the genetic factors that predispose individuals to sporadic thoracic aortic disease (TAD) in the absence of clear pathogenic genetic variants. They observed that individuals with early onset sporadic disease carried variants of unknown clinical significance (VUS’s) in one or more genes known to cause TAD, although each individual variant was unlikely to cause disease. Mouse models were used to confirm this finding by showing that double variant mice developed aortic enlargement compared to mice carrying either variant individually or the WT. This study demonstrates the utility of functional testing of VUS’s as well as the need for a classification strategy for variants that act as risk factors for Mendelian disorders. This study highlights the spectrum of functional consequences of variants and emphasizes the role of partial function variants in contributing to disease risk even when those individual variants are insufficient to cause disease.
Training & Development Committee: Could you describe your research for us?
Dr. Kwartler: I work in the laboratory of Dr. Dianna Milewicz, where I study molecular mechanisms of genetically triggered vascular disease. I use mouse and cell culture models including induced pluripotent stem cell models to dissect the pathways connecting genetic variants identified in human patients with the disease pathogenesis.
TDC: What are your career goals?
Dr. Kwartler: I plan to be a principal investigator of my own laboratory and intend to focus on epigenetic regulation of smooth muscle cell fate specification. Smooth muscle cells are a diverse and plastic cell type, so understanding what drives smooth muscle cell identity will have broad implications for a number of vascular diseases.
TDC: Why did you choose genetics as your field of study?
Dr. Kwartler: I have always been fascinated by developmental genetics- how genetic and epigenetic regulation informs cell fate decisions during development. Applying that same mentality to disease pathogenesis- thinking of the transition from a healthy to diseased state as compared with the transition from a progenitor to mature state – is a powerful tool to understanding human disease. We were intrigued by the idea that a variant of unknown significance (VUS) might be identifiably deleterious without being deleterious enough to be “pathogenic,” similar to the accumulation of multiple hits thought to underlie cancer. Dr. Milewicz’s group had identified VUS in patients with thoracic aortic aneurysms, a disease for which a polygenic inheritance model had not been established. We were able to use enzymatic assays we had already established in the lab to confirm Mendelian variants in the same genes, as well as mouse models we had previously generated and extensively characterized, to test this question and identify a novel category of “risk alleles” for thoracic aortic disease.
TDC: If you could pick three words that describe yourself, what would they be?
Dr. Kwartler: Intellectual, Creative, Committed
Twitter handle: @JohnRitterPrgm
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