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 t...

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Autores principales:	Ionut-Florin Iancu, Almudena Avila-Fernandez, Ana Arteche, Maria Jose Trujillo-Tiebas, Rosa Riveiro-Alvarez, Berta Almoguera, Inmaculada Martin-Merida, Marta Del Pozo-Valero, Irene Perea-Romero, Marta Corton, Pablo Minguez, Carmen Ayuso
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/720741e99c944b1c8ee4d0d7b5c84e84
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spelling	oai:doaj.org-article:720741e99c944b1c8ee4d0d7b5c84e842021-12-02T16:23:14ZPrioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies10.1038/s41525-021-00182-z2056-7944https://doaj.org/article/720741e99c944b1c8ee4d0d7b5c84e842021-02-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00182-zhttps://doaj.org/toc/2056-7944Abstract 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.Ionut-Florin IancuAlmudena Avila-FernandezAna ArtecheMaria Jose Trujillo-TiebasRosa Riveiro-AlvarezBerta AlmogueraInmaculada Martin-MeridaMarta Del Pozo-ValeroIrene Perea-RomeroMarta CortonPablo MinguezCarmen AyusoNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Ionut-Florin Iancu Almudena Avila-Fernandez Ana Arteche Maria Jose Trujillo-Tiebas Rosa Riveiro-Alvarez Berta Almoguera Inmaculada Martin-Merida Marta Del Pozo-Valero Irene Perea-Romero Marta Corton Pablo Minguez Carmen Ayuso Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies
description	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.
format	article
author	Ionut-Florin Iancu Almudena Avila-Fernandez Ana Arteche Maria Jose Trujillo-Tiebas Rosa Riveiro-Alvarez Berta Almoguera Inmaculada Martin-Merida Marta Del Pozo-Valero Irene Perea-Romero Marta Corton Pablo Minguez Carmen Ayuso
author_facet	Ionut-Florin Iancu Almudena Avila-Fernandez Ana Arteche Maria Jose Trujillo-Tiebas Rosa Riveiro-Alvarez Berta Almoguera Inmaculada Martin-Merida Marta Del Pozo-Valero Irene Perea-Romero Marta Corton Pablo Minguez Carmen Ayuso
author_sort	Ionut-Florin Iancu
title	Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies
title_short	Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies
title_full	Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies
title_fullStr	Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies
title_full_unstemmed	Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies
title_sort	prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/720741e99c944b1c8ee4d0d7b5c84e84
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Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies

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