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Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration (RD), and the most common cause of incurable blindness diagnosed in children. It is occasionally the presenting symptom of multisystemic ciliopathies which diagnosis will require a specific care of patients. Nineteen LCA genes are currently identified and three of them account for both non-syndromic and syndromic forms of the disease.  RD3  ( LCA12 ) was implicated as a LCA gene based on the identification of homozygous truncating mutations in two LCA families despite the screening of large cohorts of patients. Here we provide a comprehensive survey of  RD3  mutations and of their clinical expression through the screening of a cohort of 852 patients originating worldwide affected with LCA or early-onset and severe RD. We identified three  RD3  mutations in seven unrelated consanguineous LCA families -  i.e. , a 2 bp deletion and two nonsense mutations – predicted to cause complete loss of function. Five families originating from the Southern Shores of the Mediterranean segregated a similar mutation (c.112C>T, p.R38*) suggesting that this change may have resulted from an ancient founder effect. Considering the low frequency of  RD3  carriers, the recurrence risk for LCA in non-consanguineous unions is negligible for both heterozygote and homozygote  RD3  individuals. The  LCA12  phenotype in our patients is highly similar to those of patients with mutant photoreceptor-specific guanylate cyclase  (GUCY2D/LCA1 ). This observation is consistent with the report of the role of RD3 in trafficking of GUCYs and gives further support to a common mechanism of photoreceptor degeneration in  LCA12  and  LCA1 ,  i.e. , inability to increase cytoplasmic cGMP concentration in outer segments and thus to recover the dark-state. Similar to  LCA1 ,  LCA12  patients have no extraocular symptoms despite complete inactivation of both  RD3  alleles, supporting the view that extraocular investigations in LCA infants with  RD3  mutations should be avoided.

plos one

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