Novel RP1 Mutations in Autosomal Recessive Retinitis Pigmentosa by targeted next generation sequencing

Abstract

Purpose : Retinitis pigmentosa (RP) is a group of rare inherited retinal dystrophy that can result in a progressive loss of vision. Molecular diagnosis of RP is difficult due to its phenotypic and genetic heterogeneities. We performed targeted next generation sequencing (NGS) in a collection of RP cases to investigate causative genetic mutations in one Indian and two Chinese families with arRP, and two sporadic patients with RP.

Methods : A total of 166 genes were found to be involved in inherited retinal disorders. We selected these genes for targeted next generation sequencing (NGS) that were performed on five index patients and 100 healthy controls . Stringent next-generation sequencing data analysis and Sanger sequencing and segregation analysis were applied to evaluate all identified pathogenic mutations.

Results : Four novel frameshift mutations (p.H1390Lfs*6; p.S953Qfs*12; p.R793Efs*55; p.I2061Sfs*12) and two compound heterozygous mutations (p.Y834*; p.R1933*) were identified in RP1. Additionally, all mutations were found to cosegregate with the disease in these three families, and none of the mutations were detected in control samples.

Conclusions : The results of this research extend the mutational spectrums of RP1 for arRP, and support the application of targeted NGS in identifying RP-causative mutations.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

 

Fig 1. Genetic finding of this study. (A-C) Pedigrees and Sanger sequencing of family ARRP-86, ARRP-93 and ARRP-59. Each pedigree shows affected (dark symbols) and unaffected (open symbols) individuals, with squares representing males and circles representing females. The propositus is indicated with oblique arrows. A slash indicates the deceased. Sanger sequencing confirmed the segregation of these mutations and arrows indicate the altered nucleotide. (D) Sanger Sequencing analysis of two sporadic patients affected with RP. Two homozygous frameshift mutations were identified. (E) Diagram showing the RP1 protein structure and position of identified mutations in this study. Exon 4 was highlighted.

 

Fig 2. Clinical examination of patient 93. (A) The visual field diagram showed severe impairment of vision field in both eyes. (B) Electroretinogram (ERG) shows a reduced or extinguished-amplitude a/b-wave, which indicates the damage of photoreceptors and impaired retinal function.