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.

Figure 1. Amino acid alignments around seven novel missense mutations.

The altered residues (marked in yellow) are fully conserved through all species in almost all cases. The aa type is color-coded: small aa in red, acidic in blue, basic in magenta, and hydroxyl + amine + basic in green.

Figure 2. Pedigrees of 4 families discussed in details in the paper.

The family number and the mutated gene/s are noted above each pedigree. The genotype for each mutation is listed below each individual’s symbol. Consanguinity is marked by double lines.

Figure 3. Fundus phenotype of three affected individuals of MOL1145 with a homozygous CDH3 mutation.

(A) Fundus appearance of individual III:3. At the age of 34 years, he demonstrates narrowed blood vessels, waxy pallor of the optic nerve, bone-spicule like pigmentations, typical for RP, and severe macular atrophy. His brother III:4 (B) and sister III:6 (C) at the age of 30 and 33 respectively, demonstrated the same fundus appearance, but with less bone spicule-like pigmentations.

Figure 4. Genetic architecture of autosomal recessive IRDs in the Israeli and Palestinian populations.

The number of families with mutations in the related gene is indicated below the gene symbol.