Molecular analysis of foveoschisis in females reveals a novel case of segmental uniparental disomy in X-linked retinoschisis.

Background: Foveoschisis refers to the splitting of retinal layers involving the macula that may have different causes with variable structural-functional natural histories. Idiopathic cases are seen in the absence of inherited or acquired predisposing conditions and referred to as stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR). Our study aimed to clinically and genetically characterize females presenting with foveoschisis (including affected male siblings where present).

Methods: Five patients (3 females and 2 males) from 3 consanguineous families presenting with foveoschisis underwent complete ophthalmological evaluation, multimodal imaging including color, infrared, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT), electroretinogram (ERG), and molecular evaluation including Sanger sequencing of the RS1 gene and whole exome sequencing (WES). Main outcome measures were age at first visit, best-corrected visual acuity (BCVA), peripheral retinal changes, FAF pattern, ERG findings, and RS1 variants.

Results: The mean age was 21.8 years. The BCVA ranged from 20/100 to 20/20. Peripheral retinal changes ranged from a tapetal reflex, peripheral retinoschisis, vitreous veils, to vitreoretinal traction. A ring of increased signal was the most common FAF abnormality, while one patient exhibited a double-ring hyperautofluorescence. All patients demonstrated an electronegative ERG. One female was considered to have a molecularly undiagnosed inherited retinal disease (IRD). Another female was considered stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR) after exclusion of other causes. Three patients showed a novel nonsense variant in the RS1 gene; homozygous in the female sibling and hemizygous in the male siblings. Familial segregation revealed an unaffected father and a carrier mother. Trio SNP array confirmed maternal segmental uniparental isodisomy (seg UPiD).

Conclusion: This is the first reported X-linked retinoschisis (XLRS) case with seg UPiD. We emphasize the significance of SNP arrays in elucidating non-Mendelian inheritance cases. We report a novel variant, which is the first to be detected in the RS1 domain in a female.