Purpose: The purpose of this study was to elucidate the genetic basis of 2 distinct phenotypes associated with biallelic variants in RDH12.
Methods: Patients with biallelic variants in RDH12 were recruited from our genetic eye clinic. Ocular phenotypes were evaluated. Genotype-phenotype correlations were further clarified using in-house and existing databases.
Results: In total, 22 biallelic RDH12 variants, including 5 novel variants, were identified in 29 patients from 27 families. Two distinct phenotypes were observed: early-onset and generalized retinal dystrophy with severe impairment of rods and cones in 24 patients (82.8%, 24/29), and late-onset cone-rod dystrophy (CORD) with central macular atrophy in 5 patients from 5 unrelated families (17.2%, 5/29), in which a hypomorphic allele (c.806C>G/p.Ala269Gly) was shared by all 5 patients. During follow-up, patients with late-onset CORD were relatively stable and did not progress to the severe form, which was considered to be an independent manifestation of RDH12-associated retinopathy caused by specific genotypes.
Conclusions: The hypomorphic allele is responsible for the unique late-onset CORD in 5 families with recessive RDH12-associated retinopathy, in contrast to the well-known severe and generalized retinopathy. Determining the therapeutic value of interventions may depend on understanding the molecular mechanisms underlying manifestation of this hypomorphic variant only in the central macular region, with relative preservation of the peripheral retina.