A Korean Patient With Leber Congenital Amaurosis and a Homozygous RPE65 Variant Originating From a Paternal Uniparental Isodisomy.

Background: Leber congenital amaurosis (LCA), the most severe form of inherited retinal dystrophy, is a rare, heterogeneous, genetic eye disease associated with severe congenital visual impairment. RPE65, one of the causative genes for LCA, encodes retinoid isomerohydrolase, an enzyme that plays a critical role in regenerating visual pigment in photoreceptor cells.

Methods: Exome sequencing (ES) was performed on a patient with suspected LCA.

Results: Here, we report a 33-year-old male patient diagnosed with RPE65-related LCA caused by uniparental isodisomy (UPiD) who received gene therapy as treatment, fourth patient to receive it in Korea. His fundus examinations showed salt-and-pepper retinal dystrophy, with diffuse extinguished signal on fundus autofluorescence and attenuated amplitude on electroretinogram. A homozygous frameshift variant NM_000329.3:c.1067del (p.Asn356MetfsTer17) in RPE65 was identified by ES with the entire chromosome 1 proving to be paternal UPiD. Within 5 months after the molecular diagnosis, the patient was treated with subretinal voretigene neparvovec (VN) therapy and is being followed up for prognosis.

Conclusions: To our knowledge, this patient is the first UPiD case to receive VN treatment. Performing ES as a first-tier test was favourable because it allowed to identify UPiD that needed to be detected in addition to the disease-causing variant.