The First Person section highlights a member of the Division of Genetic and Genomic Medicine who recently published a peer-reviewed paper. For the inaugural edition, we invite Olivia D'Annibale, a Ph.D. candidate in the Vockley Lab to tell us about her newest paper and interest outside of the lab.
Characterization of variants of uncertain significance in isovaleryl-CoA dehydrogenase identified through newborn screening: An approach for faster analysis
Olivia M. D’Annibale et al. Molecular Genetics and Metabolism, August 2021 (PMID: 34535384)
How would you explain the main findings of your paper to non-scientific family and friends?
Typically when a variant of uncertain significance (VUS) is found during follow-up sequencing after newborn screening (NBS), there is a long process to determine if that VUS is harmful or not. Normally, a skin biopsy is performed on the patient and fibroblasts are isolated and grown. We then can perform functional studies to determine how much protein and enzyme activity is in that patient's fibroblast. This process takes a long time and sometimes fibroblast samples are not available. Here, we used CRISPR/Cas technology to delete part of the IVD gene in a HEK293T cell line to generate a null line with no IVD protein or activity.
How did you start working on this project?
We were interested in figuring out a faster way to determine pathogenicity for mutations in isovaleryl-CoA dehydrogenase (IVD). I also had some free time in lab while my other projects were going on or needed trouble shooting. A previous fellow and post-doc had already generated the IVD null HEK293T cell line, but were not able to finish the follow up experiments. Dr. Vockley also had several IVA patient samples containing VUS that needed analyzed, so it was a great opportunity to wrap up this project and answer pending questions.
What about this paper that excites you the most?
This paper excites me because it has an immediate impact on how IVA is managed. The faster we can identify VUS in IVD and determine pathogenicity, the faster the patient can begin the best treatment plan. The ability for this to be determined in a month rather than 6 months to a year is huge for these kids. Since IVA is detected on newborn screening, the faster a treatment plan can be implemented, the less adverse side affects the child experiences.
Thinking about the bigger picture, what implications do you see from this work for the larger genetics and genomic medicine and/or pediatric community?
This research really helps to answer a major problem in the field. There are hundreds of variants for IVD in the ClinVar Database that are classified as a VUS. Not every mutation has a corresponding fibroblast to perform functional studies on, nor does the Vockley lab have access to these fibroblasts. So, this project allows us to bypass that fibroblast collection step and speed up the analysis process. It also allows us to pinpoint each mutation individually instead of looking at two mutations in the same cell line. This paper also allows for the expansion of this project to use this model to look at other genes that correspond to acyl-CoA dehydrogenase (ACAD) deficiencies such as very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency which also has a high amount of VUS.
What’s next for you?
I am currently preparing to defend my dissertation in February. I have accepted a Clinical Biochemical Genetics fellowship in Denver, Colorado that I am starting July 2022! I also have plans to travel for the SIMD and ACMG conferences in Spring 2022 to present my dissertation research. I am hoping to wrap up any loose ends in the Spring after my defense.
For fun, tell us something about your life outside of the lab.
I enjoy watching the latest binge-worthy Netflix show. I have also been searching for a new hobby so I have tried out traditional painting, diamond paintings, keeping plants alive, and peaceful walks around Pittsburgh. I also document the food I eat out in Pittsburgh and Erie, PA on Instagram so that I can remember the great places I’ve eaten at.