Abstract

Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy, and 15–25% of RP is transmitted as an autosomal dominant (ad) trait. The objectives of this study were to establish the variant profile in a large cohort of adRP families and to elucidate the variant spectrum of each adRP gene in Chinese patients. A total of 138 probands clinically diagnosed with RP as a presumed autosomal dominant trait were recruited. All probands underwent ophthalmic examinations by specialists. A combination of molecular screening methods, including targeted next-generation sequencing, Sanger DNA sequencing, and multiplex ligation probe amplification assay, was used to detect variants. We identified heterozygous variants of 11 adRP genes in 73 probands, hemizygous, or heterozygous variants of X-linked RP genes in six patients, compound heterozygous variants of autosomal recessive RP genes in three pseudodominant families, and one heterozygous variant of one ad cone and rod dystrophy gene in one proband. One proband was found carrying both variants in RPGR and FAM161A. The overall detection rate was 59.4% (82/138). We detected 72 distinct disease-causing variants involving 16 RP genes and one cone-rod dystrophy gene; 33 of these variants have not been reported previously. Disease-causing variants were identified in the adRP genes in 52.9% of the families, followed by 4.3% in the X-linked RP genes, and 2.2% in the autosomal recessive genes. The most frequent mutant genes were RHO, PRPF31, RP1, SNRNP200, and PRPF8, which explained up to 78.0% of the genetically diagnosed families. Most of the variants identified in adRP genes were missense, and copy number variations were common (7/20) in the PRPF31 gene. We established the profile of the mutated genes and the variant spectrum of adRP genes in a large cohort of Chinese patients, providing essential information for genetic counseling and future development of therapeutics for retinal dystrophy inherited as a dominant trait.

Highlights

  • Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy (IRD), with a prevalence of about 1 in 4,000 (Ayuso and Millan, 2010)

  • We have described the outcomes of a comprehensive molecular analysis of 138 pedigrees with possible adRP by a combination of methods, including targeted exome sequencing (TES), Sanger sequencing, and real-time quantitative polymerase chain reaction (q-PCR) analysis or multiplex ligation-dependent probe amplifications (MLPAs)

  • We found a total of 72 different variants in 17 genes, including 11 adRP genes, two xlRP genes, three arRP genes, and one autosomal dominant cone and rod dystrophy gene (Figure 1)

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Summary

INTRODUCTION

Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy (IRD), with a prevalence of about 1 in 4,000 (Ayuso and Millan, 2010). Patients were diagnosed with RP based on the following criteria: a history of night blindness, progressive visual field defects, fundus displaying bone spiculelike pigment clumping in the midperipheral or peripheral retina and attenuation of retinal vessels, and severe rod-cone dysfunction or non-recordable ERG recording (Ayuso and Millan, 2010). Five exons and flanking splicing sites of the RHO gene were first sequenced for all probands diagnosed with adRP, except for the four families that we have previously reported (Pan et al, 2012; Dong et al, 2013). We performed TES in 113 patients who did not carry any RHO variants using a capture panel developed and evaluated by our group (Sun et al, 2018) This panel comprised 188 known IRD genes, and 26 of them were adRP genes. MLPA assays were conducted for three probands and their family members using the SALSA MLPA Kit P235 (Amsterdam, the Netherlands), following the producer’s protocols

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