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

Ionut-Florin Iancu,Marta Del Pozo-Valero,Rosa Riveiro-Alvarez,Carmen Ayuso,Ana Arteche,Inmaculada Martin-Merida,Marta Corton,Irene Perea-Romero,Pablo Minguez,Berta Almoguera,Maria Jose Trujillo-Tiebas,Almudena Avila-Fernandez

doi:10.1038/s41525-021-00182-z

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.

Highlights

Inherited retinal dystrophies (IRD) are a group of degenerative and progressive diseases caused by primary affection of photoreceptors and retinal pigmentary epithelium cells[1]
The frequency of variants of uncertain significance (VUS) reporting in IRD differs according to the inheritance pattern and causative genes
To determine whether the type of disease or our expertize in IRD cases influenced the degree of successful diagnosis of cases, we compared the rates of diagnosis status in the IRD and non-IRD cohorts

Summary

INTRODUCTION

Inherited retinal dystrophies (IRD) are a group of degenerative and progressive diseases caused by primary affection of photoreceptors and retinal pigmentary epithelium cells[1]. Jiménez Díaz (HU-FJD), the percentage of unsolved cases pending at least one VUS reclassification is about 17% of all IRD families analyzed Reclassifying these variants would doubtless have a substantial impact on the clinical management of patients. There are several approaches that can be used to follow up and reclassify a VUS: (i) in vivo and/or in vitro functional assessment tests to mimic the mutation and observe phenotype changes[10,11]; (ii) cumulative evidence from other cases identified as having the same VUS and phenotype[12]; and (iii) the segregation of the variant within the family These approaches have obvious limitations, including a delay in diagnosis, which is one of the major challenges in rare diseases, as they postpone appropriate clinical management for an average of five years[13].

RESULTS

DISCUSSION

CODE AVAILABILITY