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Elise Heon, Marcela Perez-Araya, Heather Trang, Chelsea Roadhouse, Ajoy Vincent; is the predominant LCA gene in a Canadian ethnically diverse LCA patient population.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3847.
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© ARVO (1962-2015); The Authors (2016-present)
To ascertain the relative contribution of the 17 known LCA genes to the LCA disease load in an ethnically diverse population of patients assessed at The Hospital for Sick Children, Toronto
Patients were identified using the Ocular Genetic Database when carrying a clinical diagnosis of LCA or having disease causing muatations in any of the 17 known LCA-related genes A retrospective chart review was subsequently performed. Only patients with clinically and molecularly confirmed LCA were included for analysis.<br />
Sixty six LCA patients had 2 pathogenic mutations (autosomal recessive) in 12 different genes; one patient had autosomal dominant disease associated with CRX. There was no gender bias. The gene most frequently involved was RPE65, accounting for 35.8% of our patients (24/67 patients). The most prevalent RPE65 mutation was R91W (9 patients, 17 alleles); found most commonly in consanguineous families of of Somalian, Italian, Caribbean and Chinese (Hong Kong) origin. CRB1 was the second most common gene causing LCA, accounting for 16.4% (11/67) of the cases. NMNTA1 mutations were found in 9% of patients (n=6), while mutations in CEP290, AIPL1 and GUCY2D accounted each for 6% of cases (n=4). The commonly seen intronic CEP290 mutation (c.2991+1655A-->G) in other studies was not observed. No mutations were identified in LCA5, IMPDH1, LRAT, KCNJ13 or GDF6. Twenty eight ancestral origins were represented, the most common being the British Isles (19%), followed by Pakistan (12%), Italy (8%) and East India (8% ). Our cohort had 33 patients from consanguineous marriages but only 12 families with 2 or more affected cases were observed. All but one consanguineous families harbored homozygous variants. Forty one cases were sporadic; 23 mutations were novel at the time of analysis. The pathogenicity of the novel variants were validated using publicly available predictive algorithms, segregation analysis and ethnic specific allele frequency data when possible. Different mutations in CRB1, GUCY2D, TULP1, and CRX were associated with an early onset retinal dystrophy phenotype and these were not included in this analysis.
In our cohort RPE65 is the gene most commonly associated with LCA. The difference from previous studies in the contribution of RPE65 and CEP290 mutations to LCA, could relate to the ancestral background of patients studied.
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