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A research study of Stargardt disease (STGD1) highlights inter-sibling variability between genotype-phenotype

Research at the Radboud University Medical Centre in Nijmegen, the Netherlands, has reported a phenotypic discordance between siblings with STGD1 having the same ABCA4 variants.  While fundus autofluorescence images appear to compare phenotypic outcomes between siblings, the study identifies substantially different functional outcomes. The research study may throw up significant challenges for clinical management and clinical trial research on how new treatments may be monitored in interventional and non-interventional studies.  Innovative trial designs may need to be required to consider how data captures the heterogeneity of such outcomes, especially in orphan disease populations where patient recruitment is always challenging.


Stargardt disease (STGD1) has an estimated prevalence of 1/10,000 caused by variants in the ABCA4 gene, an autosomal recessive retinal dystrophy characterized by central retinal degeneration. According to the literature, to date, there are more than 900 unique variants reported in ABCA4-related retinopathies, of which 50% variants are missense mutations.  In the current study, results showed major differences in the age-at-onset were present in 5 of 17 families, ranging from 13 to 39 years. According to the analysis, 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. The researchers additionally 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 11.38mm2 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. Finally, qualitative fundus autofluorescence images and spectral-domain OCT phenotypes were also highly comparable between siblings.


From the data, the Dutch researchers suggested that familial discordance is a prevalent phenomenon in STGD1 and this outcome should be important in patient counselling for patient clinical management.  The study also found a difference in age-at-onset of 10 years or more between siblings in 5 families, ranging from 13 to 39 years, and that in each of these families, the highest age at onset was reported by male patients.  In summarising their research, the report stated that “these findings can potentially be explained by the presence of currently unidentified environmental and genetic modifying factors that complicate sibling-based prognosis further. Therefore, patient management should be aimed at identifying the individual disease phenotype, and ophthalmologists should be cautious about using sibling information in patient prognosis”.