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Large European sample of autosomal dominant retinitis pigmentosa (adRP) families reveal landscape of genetic mutations behind pathology

Researchers, based at the Department of Genetics, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital–Universidad Autónoma in Madrid, have published research on the spectrum of mutations and genes involved in autosomal dominant retinitis pigmentosa (adRP). The research was carried out on 258 unrelated Spanish families with a clinical diagnosis of RP and suspected autosomal dominant inheritance.   The findings, published in the journal IOVS (, demonstrate the capability of defining 60% of genetic causes using a variety of classical and next generation diagnostics.


Historically, a broad number of clinical diagnoses of RP were genetically “unknown”, given limitations in technology and resources however, the Spanish study now indicates that with current tools, 60% of families were able to receive a genetic diagnosis. The landscape of the varying mutations and genes involved provide a valuable data set not only for the immediate families but also for planning of potential gene therapy opportunities and healthcare requirements. Altogether, a total of 114 different SNVs (single nucleotide variants) and CNVs (copy number variants) were identified: the most prevalent mutations seen were p.(Pro347Leu) in the RHO gene, followed by p.(Gly56Arg) in the NR2E3 gene; mutations in 26 different genes were identified – 17 adRP-related genes in 138 families (53.5%), 1 autosomal dominant late-onset retinal degeneration gene in 4 different families (1.6%), 3 X-linked RP associated genes in 8 families (3.1%), and 5 different autosomal recessive IRD associated genes in 5 families (1.9%). Four adRP-associated genes accounted for 62% (96/155) of the RP in the collected families, with the rhodopsin gene (RHO) being the most prevalent, followed by PRPF31, RP1, and PRPH2. In addition, the research indicated that most of the adRP-associated causal variants were missense, except for PRPF31, RP1, CRX, and TOPORS, where loss-of-function variants were most prevalent. Mutations in RHO and PRPF31 were the most prevalent, explaining 21% and 8% of the Spanish families causative genetic origin, followed by RP1 and PRPH2. Of particular interest, was the finding of CNVs as a pathogenic cause behind several families etiology – CNVs refer to structural variation involving DNA segments larger than 1 kilobase in which there is a relative gain or loss of copy number, relative to a reference genomic sequence. In the study, eight CNVs affecting three different adRP genes in seven unrelated families were identified. The prevalence of CNVs was 3.1% (8/258), accounting for 5% (8/160) of all the identified variants.


In concluding their study, the Spanish research group stated that, “the combination of different strategies in adRP molecular testing over time has allowed us to achieve high diagnostic rates in our Spanish cohort. Our study confirms the great diagnostic value of gene panel–based NGS (next generation sequencing) tools, which currently represent the most reliable, cost-effective, and efficient approaches for identifying not only disease-causing SNVs, but also CNVs in adRP families.”