Natural history and biomarkers of retinal dystrophy caused by the biallelic TULP1 variant c.148delG

To report clinical features and potential disease markers of inherited retinal dystrophy (IRD) caused by the biallelic c.148delG variant in the tubby-like protein 1 (TULP1) gene.

A retrospective observational study of 16 IRD patients carrying a homozygous pathogenic TULP1 c.148delG variant. Clinical data including fundus spectral-domain optical coherence tomography (SD-OCT) were assessed. A meta-analysis of visual acuity of previously reported other pathogenic TULP1 variants was performed for reference.

The biallelic TULP1 variant c.148delG was associated with infantile and early childhood onset IRD. Retinal ophthalmoscopy was primarily normal converting to peripheral pigmentary retinopathy and maculopathy characterized by progressive extra-foveal loss of the ellipsoid zone (EZ), the outer plexiform layer (OPL), and the outer nuclear layer (ONL) bands in the SD-OCT images. The horizontal width of the foveal EZ showed significant regression with the best-corrected visual acuity (BCVA) of the eye (p < 0.0001, R²  = 0.541, F = 26.0), the age of the patient (p < 0.0001, R²  = 0.433, F = 16.8), and mild correlation with the foveal OPL-ONL thickness (p = 0.014, R²  = 0.245, F = 7.2). Modelling of the BCVA data suggested a mean annual loss of logMAR 0.027. The level of visual loss was similar to that previously reported in patients carrying other truncating TULP1 variants.

This study describes the progression of TULP1 IRD suggesting a potential time window for therapeutic interventions. The width of the foveal EZ and the thickness of the foveal OPL-ONL layers could serve as biomarkers of the disease stage.