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Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies.


ABSTRACT: Inherited retinal dystrophies (IRD) are a highly heterogeneous group of rare diseases with a molecular diagnostic rate of >50%. Reclassification of variants of uncertain significance (VUS) poses a challenge for IRD diagnosis. We collected 668 IRD cases analyzed by our geneticists using two different clinical exome-sequencing tests. We identified 114 unsolved cases pending reclassification of 125 VUS and studied their genomic, functional, and laboratory-specific features, comparing them to pathogenic and likely pathogenic variants from the same cohort (N?=?390). While the clinical exome used did not show differences in diagnostic rate, the more IRD-experienced geneticist reported more VUS (p?=?4.07e-04). Significantly fewer VUS were reported in recessive cases (p?=?2.14e-04) compared to other inheritance patterns, and of all the genes analyzed, ABCA4 and IMPG2 had the lowest and highest VUS frequencies, respectively (p?=?3.89e-04, p?=?6.93e-03). Moreover, few frameshift and stop-gain variants were found to be informed VUS (p?=?6.73e-08 and p?=?2.93e-06). Last, we applied five pathogenicity predictors and found there is a significant proof of deleteriousness when all score for pathogenicity in missense variants. Altogether, these results provided input for a set of rules that correctly reclassified ~70% of VUS as pathogenic in validation datasets. Disease- and setting-specific features influence VUS reporting. Comparison with pathogenic and likely pathogenic variants can prioritize VUS more likely to be reclassified as causal.

SUBMITTER: Iancu IF 

PROVIDER: S-EPMC7902814 | BioStudies | 2021-01-01

REPOSITORIES: biostudies

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