Canonical splice site variants: more than meets the eye

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).