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Purpose The molecular diagnosis of autosomal recessive Retinitis Pigmentosa (arRP) is challenging because of the large genetic and clinical heterogeneity of this disease: to date, 36 arRP genes as well as 3 loci have been identified accounting for approximately 60 % of arRP families. Two major genes, USH2A and EYS, are responsible for 13 to 19 % of the cases, the other genes being minority. Here, we developed a strategy to search for new genes/loci causing arRP in a series of consanguineous families. Methods Inbred families were genotyped using microsatellite markers specific for USH2A and EYS genes. Families resulting from this first screening were analyzed using 250K SNP microarrays with TASE software (Transmitted Allele Search Engine). Known genes in homozygous regions were PCR/sequenced. Whole Exome Sequencing is running for a few families. Results A total of 44 inbred families were analyzed. Among them, 14 (32 %) were fully or partly homozygous for EYS or USH2A markers. We selected 16/30 of the remaining families for SNPs genotyping and homozygosity mapping. We found the causative mutation in 7 families (43 %) in a known gene (RP1, RLBP1, NR2E3, CNGB1, IMPG2, PDE6A) while in 6 others sequencing of known genes in homozygous regions is still ongoing. For the 3 remaining families, potentially new loci were found (in chromosomes 3, 10 and 21) for which the results of whole exome sequencing is being analysed. Conclusion About 43 % of the tested consanguineous families had a positive molecular diagnosis and a candidate gene approach is ongoing for the 3 loci. [ABSTRACT FROM AUTHOR]

Purpose Autosomal dominant retinitis pigmentosa (adRP) affects approximately 1 in 12,000 individuals. To date, 24 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 The 10 most frequently mutated adRP genes (in full for RHO and RDS, in hot spots only for PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3 and SNRNP200) were screened by systematic sequencing to determine the causative mutation in a cohort of 232 French families affected by adRP. We also performed a pilot experiment on 12 families by using whole exome sequencing (WES). Results The direct sequencing approach was performed on 232 proband DNAs. A causative mutation was found for 99 families (42.7 %), among which 35 out of 68 (51.5 %) were novel. Among the 133 remaining families with no mutation (57.3 %), 12 probands were subjected to WES. This allowed to identify 7 additional families with a causative mutation. Conclusion The prevalence of the genes was similar to that of the literature for most genes (e.g. RHO with 16 %), but were unexpected for others (e.g. NR2E3 with 3.9 %). The WES approach allowed us to identify a causative gene in 58.3 % of a population previously screened by direct sequencing approach. The 5 remaining families, negative with WES screen, are potentially carrying a mutation in one or more new adRP genes although an intronic mutation cannot be excluded. These 5 families are under active investigation. [ABSTRACT FROM AUTHOR]