022 Functional genomics and transcriptomics further characterise and potentially improve diagnostic yield of hereditary ataxias

Up to 60–74% of patients with hereditary ataxia (HA) remain undiagnosed even following whole genome sequencing. We leveraged publicly-available -omics data to generate 299 genic features, capturing information about: gene structure/complexity; genetic variation; tissue-specific, cell-specific and tempo- rally-relevant gene expression/co-expression and protein products. Using existing age-of-onset informa- tion, we categorised HA-linked genes as childhood-onset, adult-onset and those overlapping both. By comparing the properties of childhood- and adult-onset genes, we demonstrated: (i) an unexpectedly high short tandem repeat (STR) density within childhood-onset genes suggesting that we may be missing pathogenic STRs within this cohort; (ii) significant similarities in annotation across the groups suggesting adult- and childhood-onset patients should be screened for mutations using a common gene set. We tested the latter hypothesis within the Genomics England 100,000 Genomes Project by assessing the burden of potentially pathogenic variants among childhood-onset genes in adult-onset HA patients and vice versa. This demonstrated a significantly higher burden of rare potentially pathogenic variants in the childhood-onset HA genes POLR3A and SACS amongst individuals with adult-onset HA. Thus, our analysis would suggest that a broader testing strategy for HAs particularly in adult-onset patients could increase diagnostic yield and highlights genic features of interest to exp...
Source: Journal of Neurology, Neurosurgery and Psychiatry - Category: Neurosurgery Authors: Tags: Live Poster, 6 May SIG4: Movement Disorders Source Type: research