Targeted Next Generation Sequencing Reveals a Novel Frameshift MERTK Mutation in Retinitis Pigmentosa

Abstract

Purpose : Retinitis pigmentosa (RP) is a group of inherited retinal diseases that causes severe progressive visual impairment. The purpose of this paper was to apply targeted next-generation sequencing (NGS) to identify causative mutations of RP in a Chinese RP family.

Methods : Blood samples were collected from a 30-year-old female Chinese proband diagnosed with RP and her family members. A total of 163 genes that have been found to be involved in inherited retinal diseases were selected for NGS. Rigorous NGS data analysis, Sanger sequencing validation and segregation analysis were applied to evaluate identified pathogenic mutations.

Results : Sequence analysis revealed that the proband and her affected sister both carried a novel homozygous frameshift mutation in MERTK (p.I103Nfs*4). Other family members carrying a heterozygous mutation were unaffected. This mutation was found to cosegregate with the disease phenotype in this family. In addition, this mutation was not found in 1,000 control samples.

Conclusions : The targeted NGS strategy is an efficient tool for RP pathogenic gene detection. This study identified a new autosomal recessive mutation in the RP-related gene MERTK, which expanded the spectrum of RP disease-causing mutations.

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

 

Fundus examination of the proband showing moderate bone-like pigmentation, constricted retinal vessels and pallor of the optic disc in both eyes. (a) Patient’s left eye. (b) Patient’s right eye.

 

Pedigree and DNA sequence chromatogram of the family. (a) The pedigree of this family. The proband is marked by an arrow. Shaded symbols indicate clinically manifested RP. The homozygous and heterozygous mutations are shown as M/M and M/+, respectively. (b,c) Sequence analysis of the MERTK gene in the proband (04) and her affected sister (05) reveals a novel RP mutation, c.304_305delCA, resulting in a subsequent frameshift reading frame and truncated protein. (d-f) Sequence analysis of the MERTK gene in three unaffected family members (01, 02 and 03) reveals the heterozygous mutation was non-pathogenic. Arrows indicated the start position of altered nucleotides.