Highly Variable Disease Courses in Siblings with Stargardt Disease

Ophthalmology. 2019 Dec;126(12):1712-1721. doi: 10.1016/j.ophtha.2019.07.010. Epub 2019 Jul 16.


Purpose: To investigate intersibling phenotypic concordance in Stargardt disease (STGD1).

Design: Retrospective cohort study.

Participants: Siblings with genetically confirmed STGD1 and at least 1 available fundus autofluorescence (FAF) image of both eyes.

Methods: We compared age at onset within families. Disease duration was matched to investigate differences in best-corrected visual acuity (BCVA) and compared the survival time for reaching severe visual impairment (<20/200 Snellen or >1.0 logarithm of the minimum angle of resolution [logMAR]). Central retinal atrophy area was quantified independently by 2 experienced graders using semiautomated software and compared between siblings. Both graders performed qualitative assessment of FAF and spectral-domain (SD) OCT images to identify phenotypic differences.

Main outcome measures: Differences in age at onset, disease duration-matched BCVA, time to severe visual impairment development, FAF atrophy area, FAF patterns, and genotypes.

Results: Substantial differences in age at onset were present in 5 of 17 families, ranging from 13 to 39 years. Median BCVA at baseline was 0.60 logMAR (range, -0.20 to 2.30 logMAR; Snellen equivalent, 20/80 [range, 20/12-hand movements]) in the right eye and 0.50 logMAR (range, -0.20 to 2.30 logMAR; Snellen equivalent, 20/63 [range, 20/12-hand movements]) in the left eye. Disease duration-matched BCVA was investigated in 12 of 17 families, and the median difference was 0.41 logMAR (range, 0.00-1.10 logMAR) for the right eye and 0.41 logMAR (range, 0.00-1.08 logMAR) for the left eye. We observed notable differences in time to severe visual impairment development in 7 families, ranging from 1 to 29 years. Median central retinal atrophy area was 11.38 mm2 in the right eye (range, 1.98-44.78 mm2) and 10.59 mm2 in the left eye (range, 1.61-40.59 mm2) and highly comparable between siblings. Similarly, qualitative FAF and SD OCT phenotypes were highly comparable between siblings.

Conclusions: Phenotypic discordance between siblings with STGD1 carrying the same ABCA4 variants is a prevalent phenomenon. Although the FAF phenotypes are highly comparable between siblings, functional outcomes differ substantially. This complicates both sibling-based prognosis and genotype-phenotype correlations and has important implications for patient care and management.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Adolescent
  • Adult
  • Age of Onset
  • Child
  • Child, Preschool
  • Electroretinography
  • Female
  • Fluorescein Angiography
  • Follow-Up Studies
  • Genetic Association Studies
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Retrospective Studies
  • Siblings*
  • Stargardt Disease / genetics*
  • Stargardt Disease / pathology*
  • Tomography, Optical Coherence
  • Vision Disorders / pathology
  • Visual Acuity / physiology
  • Young Adult


  • ABCA4 protein, human
  • ATP-Binding Cassette Transporters