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. 2022 Jul 29;23(15):8431.
doi: 10.3390/ijms23158431.

Aggregated Genomic Data as Cohort-Specific Allelic Frequencies can Boost Variants and Genes Prioritization in Non-Solved Cases of Inherited Retinal Dystrophies

Ionut-Florin Iancu  1   2 , Irene Perea-Romero  1   2 , Gonzalo Núñez-Moreno  1   2   3 , Lorena de la Fuente  1   3 , Raquel Romero  1   2 , Almudena Ávila-Fernandez  1   2 , María José Trujillo-Tiebas  1   2 , Rosa Riveiro-Álvarez  1   2 , Berta Almoguera  1   2 , Inmaculada Martín-Mérida  1   2 , Marta Del Pozo-Valero  1   2 , Alejandra Damián-Verde  1 , Marta Cortón  1   2 , Carmen Ayuso  1   2 , Pablo Minguez  1   2   3
Affiliations

Aggregated Genomic Data as Cohort-Specific Allelic Frequencies can Boost Variants and Genes Prioritization in Non-Solved Cases of Inherited Retinal Dystrophies

Ionut-Florin Iancu et al. Int J Mol Sci. .

Abstract

The introduction of NGS in genetic diagnosis has increased the repertoire of variants and genes involved and the amount of genomic information produced. We built an allelic-frequency (AF) database for a heterogeneous cohort of genetic diseases to explore the aggregated genomic information and boost diagnosis in inherited retinal dystrophies (IRD). We retrospectively selected 5683 index-cases with clinical exome sequencing tests available, 1766 with IRD and the rest with diverse genetic diseases. We calculated a subcohort's IRD-specific AF and compared it with suitable pseudocontrols. For non-solved IRD cases, we prioritized variants with a significant increment of frequencies, with eight variants that may help to explain the phenotype, and 10/11 of uncertain significance that were reclassified as probably pathogenic according to ACMG. Moreover, we developed a method to highlight genes with more frequent pathogenic variants in IRD cases than in pseudocontrols weighted by the increment of benign variants in the same comparison. We identified 18 genes for further studies that provided new insights in five cases. This resource can also help one to calculate the carrier frequency in IRD genes. A cohort-specific AF database assists with variants and genes prioritization and operates as an engine that provides a new hypothesis in non-solved cases, augmenting the diagnosis rate.

Keywords: carrier frequency; gene prioritization; genetic rare diseases; inherited retinal dystrophies; variant prioritization; variants of uncertain significance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A heterogeneous cohort of rare diseases with the diagnostic status and variant composition in IRD cases. (A) The cohort of patients with suspected rare genetic diseases at the Genetics Department of HU-FJD was divided into three subcohorts. An IRD subcohort of 1766 samples, other-eye-related diseases (OERD) of 386 cases, and a pseudocontrol subcohort of non-eye-related diseases (NRD) with 3531 samples. (B) IRD diagnostic status of the samples included in IRD subcohort was solved and non-solved. The subcohort of non-solved IRD cases with no candidate variants represent the 25%. C) Flow chart of different filters applied to variants according to quality control (QC) and population (POP) filters. (D) Summary of the variants included in the database in an average IRD case; values represent the average of all IRD samples. (E) Proportion of pathogenic and VUS variants detected in IRD cases in the genes with more pathogenic variants in IRD solved cases; top 5 genes are shown.
Figure 2
Figure 2
Comparison of the percentage of deleterious variants in prioritized and non-prioritized variants in solved and non-solved IRD patients. Variant AFs are compared in inherited retinal dystrophies (IRD) solved (A) and non-solved (B) subcohorts against pseudocontrols (PC) using fold changes (FC). IRD more frequent variants (IRD-MFVs), highlighted in dark, were defined using FC thresholds at 0.90 percentiles of all FC in each comparison (A,B). Proportion of deleterious and benign variants in both solved (C) and non-solved IRD cases (D) and the p-values representing the enrichment of deleterious variants in IRD-MFVs. Enrichment analyses are also performed dividing the IRD-MFVs according to the genes in which they are located; they are grouped into IRD genes, other eye-related diseases (OERD genes), and other non-eye-related diseases (NRD genes) (E,F). Total number of deleterious variants in each group is noted at the top of the red bars. Non-significant p-values are marked as “ns”.
Figure 3
Figure 3
Genes with a higher accumulated pathogenicity in solved and non-solved IRD cases compared to pseudocontrols. Mean fold changes (FCs) in log2 scale for deleterious (Y-axis) and benign variants (X-axis) are shown for each gene. For IRD solved cases, significative genes with at least eight deleterious variants are shown in the plot (A). For IRD non-solved cases, all significative genes are shown (B).
Figure 4
Figure 4
Carrier frequency of pathogenic variants in recessive IRD genes in pseudocontrols. The carrier frequency (CF) was calculated for all IRD genes with a recessive inheritance pattern, and at least one solved case in our cohort. Green represents the CF of the genes and orange the frequency in our IRD subcohort. The pseudocontrol subcohort was composed of 3531 cases, and the IRD subcohort had 1766 cases. The top 10 genes with higher CF are ordered decreasingly.
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