Whole Exome Sequencing Reveals Mutations in Known Retinal Disease Genes in 33 out of 68 Israeli Families with Inherited Retinopathies

Abstract

Whole exome sequencing (WES) is a powerful technique for identifying sequence changes in the human genome. The goal of this study was to delineate the genetic defects in patients with inherited retinal diseases (IRDs) using WES. WES was performed on 90 patient DNA samples from 68 families and 226 known genes for IRDs were analyzed. Sanger sequencing was used to validate potential pathogenic variants that were also subjected to segregation analysis in families. Thirty-three causative mutations (19 novel and 14 known) in 25 genes were identified in 33 of the 68 families. The vast majority of mutations (30 out of 33) have not been reported in the Israeli and the Palestinian populations. Nine out of the 33 mutations were detected in additional families from the same ethnic population, suggesting a founder effect. In two families, identified phenotypes were different from the previously reported clinical findings associated with the causative gene. This is the largest genetic analysis of IRDs in the Israeli and Palestinian populations to date. We also demonstrate that WES is a powerful tool for rapid analysis of known disease genes in large patient cohorts.

Identification of genomic deletions causing inherited retinal degenerations by coverage analysis of whole exome sequencing data

“…We have recently reported that WES traditional analysis (searching for single-base substitutions as well as small insertions and deletions) revealed the identification of disease-causing mutations in known IRD genes in about one-half of cases 22. Aiming to improve WES analysis and identify homozygous and hemizygous large deletions in this set of samples, we tabulated and analysed the mean coverage for each exon in the human genome (n=185 636–194 955 exons, depending on the genome reference sequence version).…”

“…The filtering stages and their effect on the number of suspected deleted exons are detailed in online supplementary table S2. Based on these values, we analysed base coverage data of exons from 226 known IRD-causing genes 22. We excluded from the analysis exons with a relatively low MECG (lower than 9.6 which is based on mean-SD) across all samples.…”

Homozygosity for a Recessive Loss-of-Function Mutation of the NRL Gene Is Associated With a Variant of Enhanced S-Cone Syndrome

“…In one case, a homozygous patient for the c.444_445insGCTGCGGG recessive mutation was diagnosed as autosomal recessive RP, but additional clinical data were not available. 39 In a second report, two siblings, who were compound heterozygotes for two recessive NRL mutations (c.224-225insC and p.L160P), were diagnosed with a clumped pigmentary retinal degeneration. The affected patients have suffered from night blindness since early childhood, but color vision is normal, suggesting the presence of the three spectral types of cones.…”

“…36,[39][40][41][42][43][44][45][46] Electroretinography is consistent with a severe generalized rod-cone dysfunction, typical for RP, and may have an electronegative pattern. 47 Only two cases of recessive retinal dystrophies due to NRL mutations have been reported to date (Table).…”

Defining the Clinical Value of a Genomic Diagnosis in the Era of Next-Generation Sequencing

“…These initial studies clearly illustrate that some conditions are good candidate diseases for genome-scale testing; ophthalmological disorders, for example, have a diagnostic yield over 50% (18,69). By contrast, autism spectrum disorders may have a much lower yield; for example, a small study of 95 parent-proband trios had a yield of only ∼8% (119).…”