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

Purpose: 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.

Methods: 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.

Results: 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, R  = 0.541, F = 26.0), the age of the patient (p < 0.0001, R  = 0.433, F = 16.8), and mild correlation with the foveal OPL-ONL thickness (p = 0.014, R  = 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.

Conclusions: 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.