Diagnostic exome sequencing in 266 Dutch patients with visual impairment

Abstract

Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity. If no causative variants were detected and when the patient consented, the entire exome data was analyzed. A total of 266 Dutch patients with different types of inherited eye disorders, including inherited retinal dystrophies, cataract, developmental eye disorders and optic atrophy, were investigated. In the vision gene panel analysis (likely), causative variants were detected in 49% and in the exome analysis in an additional 2% of the patients. The highest detection rate of (likely) causative variants was in patients with inherited retinal dystrophies, for instance a yield of 63% in patients with retinitis pigmentosa. In patients with developmental eye defects, cataract and optic atrophy, the detection rate was 50, 33 and 17%, respectively. An exome-sequencing approach enables a genetic diagnosis in patients with different types of inherited eye disorders using one test. The exome approach has the same detection rate as targeted panel sequencing tests, but offers a number of advantages. For instance, the vision gene panel can be frequently and easily updated with additional (novel) eye disorder genes. Determination of the genetic diagnosis improved the clinical diagnosis, regarding the assessment of the inheritance pattern as well as future disease perspective.

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

“…The two most frequently mutated genes in the Israeli IRD cohort are ABCA4 (14%) and USH2A (7%). These findings are similar to those found in large IRD cohorts from other populations (Carss et al, ; Dockery et al, ; Haer‐Wigman et al, ; Stone et al, ). However, some of our findings are unique.…”

“…Overall, we succeeded to identify the genetic basis of disease in 56% of the recruited families (64% among families recruited up to December 2015). This percentage is within the range of diagnostic rates reported recently in other large cohorts of IRD patients (Carss et al, ; Dockery et al, ; Haer‐Wigman et al, ; Stone et al, ). It should be noted that of the unsolved families, only 17% have undergone WES and only 0.5% have undergone WGS.…”

1 in 38 individuals at risk of a dominant medically actionable disease

“…WES was performed following our routine diagnostic procedures [15]. In essence, DNA was outsourced to BGI (Copenhagen, Denmark) where exomes were captured using Agilent Sureselect v4 and sequenced to a median coverage of 75-fold on an Illumina HiSeq instrument with 101-bp paired-end reads.…”

EYSmutation update: In silico assessment of 271 reported and 26 novel variants in patients with retinitis pigmentosa

“…In total, we collected information of 377 RP patients described in 43 papers (Abd El‐Aziz et al., ; Abd El‐Aziz et al., ; Abu‐Safieh et al., ; Arai et al., ; Audo et al., ; Audo et al., ; Bandah‐Rozenfeld et al., ; Barragan et al., ; Beryozkin et al., ; Bonilha et al., ; Chen, et al., ; Collin et al., ; Consugar et al., ; Di et al., ; Eisenberger et al., ; Ge et al., ; Glockle et al., ; Gonzalez‐del Pozo et al., ; Gu, Tian, Chen, & Zhao, ; Habibi, et al., ; Haer‐Wigman et al., ; Hashmi, et al., ; Hosono et al., ; Huang et al., ; Huang et al., ; Iwanami, Oshikawa, Nishida, Nakadomari, & Kato, ; Jinda et al., ; Kastner et al., ; Katagiri et al., ; Khan et al., ; Littink et al., ; Littink et al., ; Neveling et al., ; Nishiguchi et al., ; Oishi et al., ; O'Sullivan et al., ; Perez‐Carro et al., ; Pieras et al., ; Pierrottet et al., ; Siemiatkowska et al., ; Suto et al., ; Xu, et al., ; Yoon et al., ), in which 630 alleles with EYS variants were reported. In addition, we identified 26 novel variants found in 36 index patients that were not published previously (Table ).…”