The diagnosis of XLRS is based on the findings of fundus examination, electrophysiologic testing and molecular genetic testing. The identification of foveal schisis in a male, associated with a reduced b-wave on ERG and a family history consistent with X-linked inheritance, makes the diagnosis very likely. Cases with subtle foveal schisis can make the diagnosis by ophthalmoscopy difficult. In these cases, Optical Coherence Tomography (OCT) can be helpful for the diagnosis.

Electrodiagnostic testing shows a characteristic electronegative ERG with a severely reduced b-wave and variation of b:a ratio in dark-adapted condition. However, a similar ERG pattern can be seen in other hereditary and acquired retinal disorders, notably, congenital stationary night blindness. It also shows a wide variability between and within families, thus it cannot be the sole investigation for XLRS.

Molecular genetic testing is available on a clinical basis and can be performed to confirm a diagnosis. RS1 is the only gene known to be associated with XRLS. Mutations can be detected in 90-95% of patients who have a clinical diagnosis when all six exons and splice junctions are sequenced. Carrier testing for at-risk female relatives, and prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies are possible if the disease-causing mutation in the family is known.

Differential diagnosis

The differential diagnoses include cytoid macular edema, retinoblastoma, Norrie disease, familial exudative vitreoretinopathy (FEVR), incontinentia pigmenti, Goldman-Favre disease, enhanced S-cone syndrome, congenital stationary night blindness, autosomal-dominant retinoschisis, acquired degenerative retinoschisis, amblyopia, retinitis pigmentosa, VCAN-related vitreoretinopathy (Wagner syndrome and erosive vitreoretinopathy).