Identification of genome-wide copy number variations using SNP genotyping arrays in patients with retinitis pigmentosa

摘要

Purpose : Retinitis pigmentosa (RP) is the most common form of inherited retinal degeneration, leading to progressive blindness. Thus far, seventy-two causative genes have been identified. However, due to an extremely genetic heterogeneity, the genetic cause of up to 30-40% patients remained unclear. Copy number variations (CNVs) are increasingly recognized as a key and potent source of genetic variation and phenotypic diversity. Here, we aimed to investigate CNVs in RP patients without detected mutation in known genes. Methods : Genome-wide CNV analyses were performed in a cohort including 50 unrelated RP patients, using the HumanCoreExome-24 BeadChip. The raw data were filtered if the genotyping call rate was less than 95%. Analyses were performed using cnvPartition CNV and GenomeStudio. All putative pathogenic CNVs were confirmed by real-time PCR. Results : All the unrelated 50 patients were initially screened by a custom-designed capture panel. None candidate mutations were found in any reported genes. Through genome-wide CNVs analyses and real-time PCR, we found that one patient harbored a heterozygous missense mutation and a 300-kb CNV in USH2A gene, from maternal and paternal allele respectively. Moreover, several rare large CNVs were identified in novel genes. Conclusions : We investigated CNVs in 50 unrelated RP patients without detected mutation in known genes. Interestingly, we demonstrated that a patient harbored a heterozygous missense mutation and a large CNV in USH2A gene. Mutations in USH2A are the major cause of RP and Usher syndrome with autosomal recessive inheritance. Targeted exome sequencing revealed only one heterozygous mutation in the RP patient, considered as a negative report. Finally, analyses of genome-wide CNVs dissected the missing genetic determinants. Our results suggested that CNVs are likely key and potent source of genetic causes of retinitis pigmentosa. This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.