Familial discordance in disease phenotype in siblings with Stargardt disease

Abstract

Purpose : To investigate intersibling discordance of the Stargardt disease (STGD1) phenotype.

Methods : We performed a retrospective cohort study among siblings with genetically confirmed STGD1 and at least one available fundus autofluorescence (FAF) image of both eyes. We compared age of onset within families using the youngest patient as the reference and a predetermined threshold value of 10 years for significant differences. Disease duration was matched to investigate differences in best-corrected visual acuity, and we determined and compared the survival time for reaching severe visual impairment (SVI); (<20/200 Snellen or > 1.3 Logarithm of the Minimal Angle of Resolution (LogMAR)). Central retinal atrophy surface area was quantified and compared by two independent graders using the semi-automated EyeNED software. Additionally, both graders performed qualitative assessment of FAF patterns to identify phenotypic differences and commonalities. Main outcome measures included differences in age of onset, best-corrected visual acuity (BCVA), time to develop legal blindness, FAF atrophy surface area and autofluorescence patterns.

Results : Significant differences in age of onset were present in 5/17 families, ranging from 13 to 39 years. BCVA was matched in 12/17 families and the median difference was 0.41 (0 – 1.10) LogMAR for the right and 0.41 (0 – 1.08) LogMAR for the left eye, and we found extreme differences in five families ranging from 0.58 to 1.1 LogMAR. The median age at which patients developed SVI was 14 years. We observed significant differences in time to develop SVI in three out of 12 families with matched survival times, ranging from 14 to 29 years. Median central retinal atrophy surface area was 11.38 mm² in the right (range 1.98 – 44.78 mm²) and 10.59 mm² in the left (range 1.61 – 40.59 mm²) eyes and was highly comparable between siblings, with the exception of family one. Qualitative FAF phenotypes were comparable in all sibling pairs.

Conclusions : Phenotypic discordance between siblings with STGD1 disease carrying the same ABCA4 variants is a prevalent phenomenon. Functional outcomes can differ substantially despite highly comparable FAF phenotypes, which complicates sibling-based prognosis. While environmental factor are likely to modify the disease course, the relatively young median age at which patients develop SVI indicates an important role for genetic factors as disease modifiers.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.