Genotype and Phenotype Studies in Autosomal Dominant Retinitis Pigmentosa (adRP) of the French Canadian Founder Population

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous blinding retinal disease, which belongs to the large group of the inherited retinal degenerations for which 54 retinal genes have thus far been found to be mutated.1 Retinitis pigmentosa commences with progressive night blindness due to rod photoreceptor disease, accompanied by gradual loss of peripheral visual field, followed by complete blindness due to cone photoreceptor degeneration. Retinitis pigmentosa has a prevalence of 1 in 3500 worldwide and may be inherited as an autosomal dominant (adRP), autosomal recessive (arRP), X-linked (XlRP), or digenic2 trait. To date, there are at least 20 genes identified to cause adRP1 and their protein products have been implicated in diverse and critical aspects of retinal photoreceptor structure and metabolism such as outer segment disc formation, the phototransduction and retinoid cycles, gene expression, transcription, mRNA processing, and others.3 According to Haim in 2002,4 the adRP form has a 42.9% prevalence in all RP cases, arRP in 41%, X-linked in 22%, and the remaining 12% of cases were presumed to be as a result of nongenetic factors, non-Mendelian inheritance (for example, mitochondrial or de novo mutations), or complex inheritance.5 The most common single gene that causes adRP is rhodopsin (RHO; MIM# 180380), which accounts for 8% to 10% of cases with more than 130 mutations identified so far.6,7 According to previously published data, inosine 5′-monophosphate dehydrogenase 1 (IMPDH1; MIM# 146690) is estimated to account for 5% to 10% of cases of adRP in the United States and Europe8; peripherin 2 (PRPH2/RDS; MIM# 179605) mutations account for 3% to 9% of adRP patients of mostly European ancestry,9–11 and retinitis pigmentosa–1 (RP1; MIM# 603937) mutations have a prevalence of 0% to 10% from various geographic origins.11,12 The human homolog of yeast pre-mRNA splicing gene (PRPF31; MIM# 606419) 1% to 8%13,14; small nuclear ribonucleoprotein 200 kDa (U5) (SNRNP200; MIM# 601664) has a prevalence at least 4.2% in the Caucasian population, and topoisomerase I-binding RS protein (TOPORS; MIM# 609507) with prevalence of 1% in European and US cohorts.13,15 The rest of the adRP genes have a much lower prevalence in the adRP cases. The most common adRP causing genes with their geographic prevalence are listed in the Table 1. Table 1 Geographic Prevalence of adRP Genes The French Canadian population, where we performed our analysis, is the so-called Quebec population and consists of 7.8 million people, 80% of which are French speaking. These current 7.8 million French Canadians descend from approximately 8500 settlers who came from France starting in 1608.16,17 The French Canadian population expanded rapidly following the British Conquest of 1759, but were relatively isolated because of religious, linguistic, and geographic barriers. During the 19th and 20th centuries, the French Canadian population was enriched by immigrants of different origins. Our cohort of 60 adRP families that we have used for our study was collected at the McGill Ocular Genetics Laboratory and Clinic (MOGL) throughout 15 years from all regions of Quebec, including very isolated areas. In the present study, based on screening of 60 families with adRP, we report the identification of 4 novel mutations in four known adRP genes in 4 affected individuals and 11 previously reported mutations in 20 affected individuals, which makes 40% of the cohort. We also report the phenotype of the four individuals carrying these novel mutations (one patient was lost to follow-up).