Inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptors. These diseases show marked phenotypic and genetic heterogeneity. The Israeli IRD consortium (IIRDC) was established in 2013 with the goal of performing clinical and genetic mapping of the majority of Israeli IRD patients. To date, we recruited 2,420 families including 3,413 individuals with IRDs. On the basis of our estimation, these patients represent approximately 40% of Israeli IRD patients. To the best of our knowledge, this is, by far, the largest reported IRD cohort, and one of the first studies addressing the genetic analysis of IRD patients on a nationwide scale. The most common inheritance pattern in our cohort is autosomal recessive (60% of families). The most common retinal phenotype is retinitis pigmentosa (43%), followed by Stargardt disease and cone/cone–rod dystrophy. We identified the cause of disease in 56% of the families. Overall, 605 distinct mutations were identified, of which 12% represent prevalent founder mutations. The most frequently mutated genes were ABCA4, USH2A, FAM161A, CNGA3, and EYS. The results of this study have important implications for molecular diagnosis, genetic screening, and counseling, as well as for the development of new therapeutic strategies for retinal diseases.

Objectives To describe the clinical phenotype and identify the molecular basis of disease in a consanguineous family of Palestinian origin with autosomal recessive retinal degeneration. Methods Eight family members were evaluated with visual acuity and perimetry tests, color fundus photographs, full-field electroretinography, and optical coherence tomography. Cone photoreceptors surrounding the fovea were imaged in 2 members, using adaptive optics scanning laser ophthalmoscopy. Exome was captured using probes and sequenced. Readings were mapped to reference hg19. Variant calls and annotations were performed, using published protocols. Confirmation of variants and segregation analysis was performed using dideoxy sequencing. Results Analysis detected 24 037 single-nucleotide variants in one affected family member, of which 3622 were rare and potentially damaging to encoded proteins. Further analysis revealed a novel homozygous nonsense change, c.1381 C>T, p.Gln461X in exon 13 of the CDHR1 gene, which segregated with retinal degeneration in this family. Affected members had night blindness beginning during adolescence with progressive visual acuity and field loss and unmeasurable electroretinographic responses, as well as macular outer retinal loss, although residual cones with increased cone spacing were observed in the youngest individual. Conclusions Exome analysis revealed a novel CDHR1 nonsense mutation segregating with progressive retinal degeneration causing severe central vision loss by the fourth decade of life. High-resolution retinal imaging revealed outer retinal changes suggesting that CDHR1 is important for normal photoreceptor structure and survival. Clinical Relevance Exome sequencing is a powerful technique that may identify causative genetic variants in families with autosomal recessive retinal degeneration.

Background Characterization of retinal degeneration (RD) using high-resolution retinal imaging and exome sequencing may identify phenotypic features that correspond with specific genetic defects. Materials and Methods Six members from a non-consanguineous Indian family (three affected siblings, their asymptomatic parents and an asymptomatic child) were characterized clinically, using visual acuity, perimetry, full-field electroretinography (ERG), optical coherence tomography and cone structure as outcome measures. Cone photoreceptors were imaged in the proband using adaptive optics scanning laser ophthalmoscopy. The exome was captured using Nimblegen SeqCap EZ V3.0 probes and sequenced using lllumina HiSeq. Reads were mapped to reference hg19. Confirmation of variants and segregation analysis was performed using dideoxy sequencing. Results Analysis of exome variants using exomeSuite identified five homozygous variants in four genes known to be associated with RD. Further analysis revealed a homozygous nonsense mutation, c.1105 C>T, p.Arg335Ter, in the FAM161A gene segregating with RD. Three additional variants were found to occur at high frequency. Affected members showed a range of disease severity beginning at different ages, but all developed severe visual field and outer retinal loss. Conclusions Exome analysis revealed a nonsense homozygous mutation in FAM161A segregating with RD with severe vision loss and a range of disease onset and progression. Loss of outer retinal structures demonstrated with high-resolution retinal imaging suggests FAM161A is important for normal photoreceptor structure and survival. Exome sequencing may identify causative genetic variants in autosomal recessive RD families when other genetic test strategies fail to identify a mutation.

No abstract