Evidence of a founder effect for the RETGC1 (GUCY2D) 2943DelG mutation in Leber congenital amaurosis pedigrees of Finnish origin

Abstract

Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies. It is a genetically heterogeneous condition as six disease-causing genes have been hitherto identified. Among them, RETGC1 (GUCY2D), is more frequently implicated in our series of LCA patients. Interestingly, 70 % of the families with RETGC1 mutations are originating from Mediterranean countries, the remaining families (30%) being originating from various countries across the world. Here, we report, the identification of the same homozygous RETGC1 nonsense mutation in three unrelated and non-consanguineous LCA families of Finnish origin, suggesting a founder effect. Interestingly, no linkage desequilibrium was found using polymorphic markers flanking the RETGC1 gene, supporting the view that the mutation is very ancient. Haplotype studies and Bayesian calculation point the founder mutation to 150 generations (95% credible interval 80-240 generations), i.e., 3000 years ago.

A founder mutation in CERKL is a major cause of retinal dystrophy in Finland

“…The finding of several founder mutations in RD reported in Table 3, and Fu et al (2013) c.2944+1delG in GUCY2D (Hanein et al 2002) (Table 1) is consistent with the population history of the Finns. Due to the small number of founders, isolation and population bottle-necks several rare genetic disorders are enriched in the Finnish population constituting the Finnish Disease Heritage (Norio 2003).…”

Union Makes Strength: A Worldwide Collaborative Genetic and Clinical Study to Provide a Comprehensive Survey of RD3 Mutations and Delineate the Associated Phenotype

“…On the other hand, several population-specific mutations were identified in LCA type I genes. In Mediterranean countries where CEP290 mutations are particularly uncommon [46]–[47], high frequencies of GUCY2D mutations resulting from founder effects have been reported [25], [37], [48]. With the present report, RD3 mutations were identified in nine consanguineous families, 6/9 of which originate from Mediterranean countries.…”

Leber congenital amaurosis: Comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis

“…Missense mutations make up the majority (16/34), followed by splice and frameshift mutations (7/34, respectively), nonsense mutations (3/34), and one inframe duplication. Five of these mutations are novel, while 29 have been reported previously [Perrault et al, 1996;El-Shanti H et al, 1999;Lorenz et al, 2000;Perrault et al, 2000;Rozet et al, 2001;Hanein et al, 2002;Lotery et al, 2003]. Five different alleles account for 36 of the 75 identified disease alleles (47.3%): 1) the c.387delC mutation was found in a homozygous state in seven unrelated patients, all born to consanguineous parents hailing from North Africa; 2) the c.2943delG deletion was identified in five unrelated patients of Finnish origin (four homozygotes) suggesting a founder effect ; 3) the p.Phe565Ser missense mutation was found to homozygously segregate in three unrelated patients of three Algerian families; 4) the c.620delC mutation was identified in two apparently unrelated consanguineous Northern African families; and finally, 5) the p.Ser448X nonsense mutation concerned two unrelated families (one consanguineous) hailing from Italy and Portugal, respectively.…”