French settlement in North America started in 1608 and occurred in mainly two regions: along the St Lawrence River (the later Quebec) and in Acadia (today corresponding to New Brunswick and Nova Scotia). The Acadians, many of whom were deported to the United States in 1755, gave rise to the later populations of Maritime Canada and to the Cajuns of the southern US. Some Acadians escaped deportation and moved to what is now Quebec. By the English conquest in 1759, French immigration stopped. Linguistic and religious barriers discouraged admixture with the mostly Protestant English-speaking new settlers. Highest birth rates occurred at pioneer fronts, that is, rural regions opened to colonization, which existed until the early 20th century. Quebec has been considered a mosaic of layered founder effects, resulting from the distinct settlers' gene pools of the respective pioneer fronts. Despite modern mobility, secularization, urbanization and immigration in the second half of the 20th century, historical founder effects still have a strong impact on medical genetics and public health in Quebec. As a result, some diseases are found more frequently or exclusively in French Canadians from Quebec than in other populations, or they have special clinical or genetic features (for example, agenesis of corpus callosum and peripheral neuropathy). Frequently, a few founder mutations account for the vast number of cases of a given phenotype [14
The genetic conditions found in Quebec are generally not found in Acadians, or they are due to different mutations (for example, oculopharyngeal muscular dystrophy) [14
]. In the case of USH1, our results challenge this point of view: we have shown that the USH1C
mutation c.216G>A, the 'Acadian allele', is the main cause of USH1 in Quebec, accounting for 40% of USH1 disease alleles and being found all along the St Lawrence River (Figure ). In Acadians, c.216G>A is responsible for virtually all USH1 cases (only one out of 44 Acadian USH1 cases has been shown not to be homozygous, but compound heterozygous for c.216G>A and c.238-239insC [17
]). The 9VNTR(t,t) in intron 5 and the c.216G>A mutation are in complete linkage disequilibrium and are almost exclusively found in Acadians, raising the possibility of a recent origin of c.216G>A in this population [17
]. Our data now strongly suggest that carriers of c.216G>A belong to the early founders of both the Acadian and the Quebec population (Figure ). This would explain its wide distribution all along the St Lawrence River valley, following the direction of the historical colonization movement (Figure ).
has so far been considered rare outside Acadia and peoples descended from that region, accounting for 7% of USH1 cases in a recent study on US and UK patients [11
]. Roux et al
] have performed extensive mutation screening in USH1 patients from France and found USH1C
mutations in only 6% of cases. Of note, c.216G>A was not detected; this resembles the rhodopsin p.P23H mutation, which has been found in 12% of Irish-American families with autosomal dominant RP, but not in Europe [22
]. Strikingly, USH1C
mutations account for 60% of USH1 in the patients investigated here, followed by CDH23
), which are responsible for the main proportion of USH1 cases in other populations, only play a minor role (one patient). To date, only six USH1-causing mutations have been identified in the USH1C
]. In our collective derived from a founder population, however, we met unexpected allelic heterogeneity: five different USH1C
mutations, including three novel (p.R155X, c.496+1G>T, and c.748_759+5del), were found. These novel changes, although probably rare in most cases and likely to be of recent origin at a given pioneer front in some, could clinically manifest because of the high prevalence of c.216G>A. Although digenic inheritance of type 1 has been described in USH1 [23
], we did not find this pattern of inheritance in our patients. Thus, there is no indication that USH1C
is involved in digenic Usher syndrome, at least probably not in combination with the other USH genes found to be mutated here.
We show that the Quebec population is the second population in the world in which USH1C
is the major genetic USH1 subtype, which is rare in all other populations studied to date. USH1 is a severely disabling disorder, causing major communication handicap due to congenital deafness and progressive retinal degeneration resulting in legal blindness in most cases. There are no official numbers describing the incidence of Usher syndrome in Quebec. However, the carrier rate of approximately 0.44% solely for the USH1C
mutation c.216G>A in the Quebec population suggests an incidence of Usher syndrome type 1C of 0.5 per 100,000 (assuming random mating and complete penetrance), based on c.216G>A alone. Assuming a minimum incidence of 1 per 1,000 for children with congenital profound hearing impairment [24
], 0.5% of these children may develop additional retinitis pigmentosa due to homozygosity for the USH1C
mutation c.216G>A. Since 60% of USH1 cases in our study are due to other mutations (20% of which also affect the USH1C
gene), and because of local founder effects (also for other USH1 subtypes such as USH1D), the incidence for USH1 may (regionally) be even higher.
While routine testing for USH1 gene mutations is hampered by the number and size of the genes involved in most populations, our data should facilitate molecular diagnosis of deafness and Usher syndrome in Quebec (>60% of cases have a mutation in USH1C and >90% of cases can be explained by ten mutations). Knowledge that a mutation in a profoundly deaf child will result in severe visual impairment in later life is important for rehabilitative strategies: parents may be more likely to choose cochlear implantation for their child rather than visual modes of communication such as sign language.
Our findings suggest that the USH1C
mutation c.216G>A is one of only a handful of common single USH1 mutations, along with founder mutations in USH3A
in the Finnish and the Ashkenazi Jewish population and a PCDH15
founder allele in Ashkenazi Jews [12
]; moreover, it is predominant in two populations. The recent development of a mouse model carrying the c.216G>A mutation in USH1C
is an important step in the development of a specific therapeutic approach for the treatment or amelioration of this devastating condition in affected individuals with the c.216G>A mutation [27