Exome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies.

María González-Del Pozo,Guillermo Antiñolo,Joaquin Dopazo,Salud Borrego,Cristina Méndez-Vidal,Nereida Bravo-Gil,Alicia Vela-Boza,Anand Swaroop

doi:10.1371/journal.pone.0116176

Abstract

This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program.

Highlights

Inherited Retinal Dystrophies (IRDs) are a group of pathologies characterized by progressive dysfunction and death of retinal photoreceptors
Molecular diagnosis of family Retinitis Pigmentosa (RP) 19 led to the clinical re-evaluation of the family since the identified ABCA4 mutations were previously related to Stargardt disease
The age of onset of symptoms (5–11 years), and the rest of clinical signs were similar to those previously reported in X-Linked RP (XLRP) patients

Summary

Introduction

Inherited Retinal Dystrophies (IRDs) are a group of pathologies characterized by progressive dysfunction and death of retinal photoreceptors. Retinitis Pigmentosa (RP [MIM 268000]) is the most common form of IRD, affecting 1:3,000 to 4,000 individuals worldwide [1, 2]. The autosomal recessive form of RP is the most common worldwide, accounting for approximately 39% of cases in Spain [4]. RP is genetically heterogeneous, with mutations in more than 60 genes and loci identified to date The contribution of most of the genes to the overall prevalence of RP is relatively small, and for the majority, only one or a few families carrying the same pathogenic mutations have been reported worldwide [5]

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