Unraveling the : Expanding the Genotypic Spectrum of Macular Pseudocoloboma.

Disease-causing variants in the gene are associated with autosomal recessive retinitis pigmentosa 90 (RP90) and Leber congenital amaurosis, with or without macular pseudocoloboma. Here, we report two patients: one compound heterozygous for c.364G>A, p.(Ala122Thr), which has conflicting classifications, and for c.293C>T, p.(Pro98Leu), which is likely pathogenic, and the other homozygous for c.364G>A, p.(Ala122Thr). This study is aimed at providing evidence to link the latter variants to a clinical phenotype. The first patient was a 6-year-old girl, and the second patient was a 29-year-old female. In both patients, the diagnostic assessments were consistent with the phenotype of RP, characterized by macular pseudocoloboma but of varying severity. Patients' phenotypes suggest that the c.293C>T, p.(Pro98Leu) variant is linked to a more severe and extensive clinical phenotype, while the c.364G>A, p.(Ala122Thr) variant results in a milder condition, primarily limited to retinal involvement. In Patient 2, the presence of both global and local stereopsis, indicating advanced visual development, suggests that the p.(Ala122Thr) missense variant may act as a hypomorphic allele which likely allows for some residual enzymatic activity of the IDH3A protein. This report highlights that macular pseudocoloboma can manifest even in the absence of a null variant. In contrast, more severe symptoms, such as mitochondrial encephalopathy, seem to be associated with the presence of a null allele. Furthermore, to the best of our knowledge, this is the first report of the c.293C>T, p.(Pro98Leu) variant.