Identification of a new locus in autosomal dominant retinitis pigmentosa and strategy for molecular diagnosis

Purpose Autosomal dominant retinitis pigmentosa (adRP) affects approximately 1 in 12,000 individuals. To date, 21 adRP genes have been identified accounting theoretically for 44.7% of adRP families; therefore, genetic defects in many patients are yet to be identified. This study was intended to provide information on prevalence of known adRP genes in France and to localize new genes and loci. Methods Microsatellite markers for the 21 adRP genes were used to genotype large families. Non excluded genes were then sequenced. For some families, we performed a whole-genome SNP analysis using Affymetrix 250K or 6.0 chips. For small families, the 8 most frequently mutated adRP genes were sequenced (in full for RHO, in hot spots only for PRPF31, RDS, RP1, PRPF8, IMPDH1, NRL and PRPF3). Results Hitherto 18 adRP families were studied by indirect genotype analysis. Of these, 15 have shown mutations in known genes and 2 are still in progress. For the last family, one new locus was identified by whole-genome SNP analysis and confirmed by microsatellite genotyping defining a 43-Mb locus on chromosome 2. The direct sequencing approach was performed on 143 proband DNAs (completely for the first 50 patients and only RHO for the 93 other patients). A causative mutation was found for 20 families (14%), among which 9 out of 11 were novel. Conclusion The preliminary results, on this limited cohort, showed that the prevalence of known genes is probably underestimated in the literature because the causative mutation was found for 15 families out of 18 (83%). However one new locus has been identified and is under active investigation.