Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies
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 differ...
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Veröffentlicht in: | Npj genomic medicine 2021-02, Vol.6 (1), p.18-18, Article 18 |
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Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 2056-7944 2056-7944 |
DOI: | 10.1038/s41525-021-00182-z |