Whole-exome Sequencing Analysis Identifies Mutations in the EYS Gene in Retinitis Pigmentosa in the Indian Population

Abstract

Retinitis pigmentosa (RP) is a rare heterogeneous genetic retinal dystrophy disease, and despite years of research, known genetic mutations can explain only approximately 60% of RP cases. We sought to identify the underlying genetic mutations in a cohort of fourteen Indian autosomal recessive retinitis pigmentosa (arRP) families and 100 Indian sporadic RP cases. Whole-exome sequencing (WES) was performed on the probands of the arRP families and sporadic RP patients, and direct Sanger sequencing was used to confirm the causal mutations identified by WES. We found that the mutations of EYS are likely pathogenic mutations in two arRP families and eight sporadic patients. Specifically, we found a novel pair of compound heterozygous mutations and a novel homozygous mutation in two separate arRP families, and found two novel heterozygous mutations in two sporadic RP patients, whereas we found six novel homozygous mutations in six sporadic RP patients. Of these, one was a frameshift mutation, two were stop-gain mutations, one was a splicing mutation, and the others were missense mutations. In conclusion, our findings expand the spectrum of EYS mutations in RP in the Indian population and provide further support for the role of EYS in the pathogenesis and clinical diagnosis of RP.

Eyes shut homolog is required for maintaining the ciliary pocket and survival of photoreceptors in zebrafish

“…The autosomal recessive retinitis pigmentosa 25 (RP25, OMIM #612424) is caused by abnormal EYS (Abd El-Aziz et al, 2008; Collin et al, 2008), a secreted extracellular matrix protein, in several populations worldwide (Abd El-Aziz et al, 2008, 2010; Audo et al, 2010; Bandah-Rozenfeld et al, 2010; Barragán et al, 2010; Chen et al, 2015; Collin et al, 2008; Di et al, 2016; Hosono et al, 2012; Littink et al, 2010b). Mutations in EYS account for 5-16% of all autosomal recessive cases in Europe (Audo et al, 2010; Barragán et al, 2010; Littink et al, 2010b) and the most prevalent form of inherited retinal dystrophy in Japan (Arai et al, 2015; Iwanami et al, 2012).…”

Ablation of EYS in zebrafish causes mislocalisation of outer segment proteins, F-actin disruption and cone-rod dystrophy

“…EYS , which spans more than 2 Mb within the RP25 locus (6q12), consists of 43 exons and encodes a 3165 amino acid protein localised in the outer segment of the photoreceptor23. Mutations in EYS are recognised as a major cause for autosomal recessive retinitis pigmentosa (arRP)4567, accounting for 5–18% arRP patients in different populations489, and have also been identified in patients with autosomal recessive cone-rod dystrophy (arCRD)1011. So far, about 100 EYS mutations, predominantly truncation mutations along with some missense mutations have been reported234567891011121314151617.…”

Identification of Compound Heterozygous EYS Variants in a Korean Patient with Retinitis Pigmentosa

“…The origin of c.9059T > C could not be elucidated because the proband's father was deceased. The c.6563T > C (p.Ile2188Thr) variant was previously reported by Arai et al [4], and the c.9059T>C (p.Ile3020Thr) variant was reported by Di et al [10].…”