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

• Published in: Npj genomic medicine Vol. 6; no. 1; pp. 18 - 9
• Main Authors: Iancu, Ionut-Florin, Avila-Fernandez, Almudena, Arteche, Ana, Trujillo-Tiebas, Maria Jose, Riveiro-Alvarez, Rosa, Almoguera, Berta, Martin-Merida, Inmaculada, Del Pozo-Valero, Marta, Perea-Romero, Irene, Corton, Marta, Minguez, Pablo, Ayuso, Carmen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.02.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/2489/144; 692/699/3161/3175; Algorithms; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Disease; Gene frequency; Gene Function; Gene Therapy; Genes; Genetics; Genomics; Human Genetics; Internal Medicine; Laboratories; Pathogenicity; Rare diseases; Reclassification; Retina
• ISSN: 2056-7944; 2056-7944
• DOI: 10.1038/s41525-021-00182-z

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.