Diagnostic application of an extensive gene panel for Leber congenital amaurosis with severe genetic heterogeneity

Leber congenital amaurosis (LCA) is a genetically heterogeneous disorder and the most severe form of inherited retinal dystrophy. We report results of a diagnostic application of an extensive gene panel composed of 204 retinal dystrophy-related genes and discuss its feasibility as a diagnostic tool. Nineteen unrelated LCA patients were included in the study: two patients for validation purposes of our gene panel, 15 previously analyzed patients with no identified mutations, and two previously unanalyzed patients. Genetic diagnosis for each patient was conducted according to whether the variants were consistent with the known inheritance pattern of each gene. We identified two heterozygous or homozygous pathogenic variants in seven of 19 patients. On the basis of mutation information, clinical features were re-reviewed, and clinical diagnoses for two patients were revised from LCA to LCA-related disorders. In addition, a coverage simulation was performed to determine the optimal depth of coverage of the gene panel. Using our gene panel, we diagnosed LCA and LCA-related disorders in 36.8% of patients and one or more deleterious variants or variants of unknown significance in 89.5% of patients. Molecular diagnosis using this extensive gene panel is expected to facilitate diagnosis of retinal dystrophy and help provide proper treatment to patients, although further analyses is needed for a complete clinical validation.