Molecular characterization of Leber congenital amaurosis in Koreans

PURPOSE Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy, and invariably leads to blindness. LCA is a genetically and clinically heterogenous disorder. Although more than nine genes have been found to be associated with LCA, they only account for about half of LCA cases. We performed a comprehensive mutational analysis on nine known genes in 20 unrelated patients to investigate the genetic cause of LCA in Koreans. METHODS All exons and flanking regions of the nine genes (AIPL1, CRB1, CRX, GUCY2D, RDH12, RPE65, RPGRIP1, LRAT, and TULP1) were analyzed by direct sequencing. We also screened our patients for the common CEP290: c.2991+1655A>G mutation found in Caucasian. RESULTS Six different mutations including four novel ones were identified in three patients (15.0%): one frameshift, one nonsense, one splicing, and three missense mutations. These patients were compound heterozygotes and harbored two different mutations in CRB1, RPE65, and RPGRIP1, respectively. We identified three novel unclassified missense variants in RPGRIP1 of the three patients. These patients were heterozygous for each variant and did not have a large deletion or duplication in the same gene. CONCLUSIONS This comprehensive mutational analysis shows marked genetic heterogeneity in Korean LCA patients and reveals a mutation spectrum that differs from those previously reported. In turn, this suggests that a different strategy should be used for the molecular diagnosis of LCA in Koreans.