Canonical splice site variants: more than meets the eye
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Dr. Costain will discuss findings from systematically assessing rare canonical splice site variants in blood expressed genes in a cohort of individuals who underwent genome sequencing and RNA-seq. The team found that up to 1 in 4 variants may not cause loss-of-function, and that in silico predictions using established tools and published guidelines were often discordant with RNA-seq data.
Overview of Presentation
- Canonical splice site variants (CSSVs) are often presumed to cause loss-of-function and are assigned very strong evidence of pathogenicity
- We identified all 168 rare CSSVs in blood-expressed genes in a cohort of 112 individuals using genome sequencing, and studied their impact on splicing using RNA sequencing (RNA-seq).
- Approximately one in four rare CSSVs did not show evidence for loss-of-function based on analysis of RNA-seq data.
- Predictions from in silico methods were often discordant with findings from RNA-seq.
- More caution may be warranted in applying very strong pathogenicity evidence to CSSVs in the absence of functional data, especially when the pre-test probability is low and phenotypes are absent or variable (e.g., secondary findings; newborn genomic screening programs).
Gregory Costain, MD, PhD
Physician-scientist
Hospital for Sick Children (SickKids)
GREGORY (GREG) COSTAIN, M.D., Ph.D., is a medical geneticist and physician-scientist at The Hospital for Sick Children (SickKids), and an assistant professor at the University of Toronto. He co-leads various genetic medicine initiatives including the SickKids Genome Board, the SickKids Translational Genomics Node of Precision Child Health, and Can-GARD (Canadian Gene Cure Advanced Therapies for Rare Disease). His research program is focused on understanding the causes and consequences of rare variation in the human genome. His lab uses genome sequencing and computational approaches to discover new disease genes, genotype-phenotype associations, and pathways to precision treatments.