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Precise genetic diagnosis in <i>RPE65</i>-mediated retinitis pigmentosa (RP) is necessary to establish eligibility for genetic treatment with voretigene neparvovec: a recombinant adeno-associated viral vector providing a functional <i>RPE65</i> gene. This case report aims to report a novel RP-related point mutation <i>RPE65</i> c.353G>A, p.(Arg118Lys), a variant of uncertain significance associated with a severe clinical presentation and the striking phenotypic feature of complete macular atrophy. We report the case of a 40-year-old male with inherited retinal dystrophy, all features typical for the <i>RPE65</i>-associated RP, and marked macular atrophy. Genetic testing identified that the patient was a compound heterozygote in <i>trans</i> form with two heterozygous variants: <i>RPE65</i> c.499G>T, p.(Asp167Tyr) and <i>RPE65</i> c.353G>A, p.(Arg118Lys). Furthermore, short-wavelength and near-infrared autofluorescence patterns exhibited deficiencies specific to mutations in the visual cycle genes. To the best of our knowledge, <i>RPE65</i> c.353G>A, p.(Arg118Lys) is the first described point mutation on this locus, among all other reported insertional mutations, currently classified as likely benign and of uncertain significance. We concluded that this variant contributed to the pathological phenotype, demonstrating its significance clearly to be reclassified as likely pathogenic. This being the case, patients with this specific variant in homozygous or compound heterozygous form would be likely candidates for genetic treatment with voretigene neparvovec.