Stargardt disease (STGD1) is an autosomal recessively inherited retinal disease (IRD) caused by variants in the ABCA4 gene, and it is characterized by degeneration of the central retina, leading to decreased visual acuity and central visual field loss. The disease is notoriously heterogeneous, leading to functional blindness in young children on the one hand, and relatively preserved visual acuity in elderly patients. To date, over 900 unique variants in the ABCA4 gene have been described, underlining the genetic heterogeneity.
The clinical and genetic heterogenic nature of STGD1 severely complicates patient prognosis. A very tempting method of trying to predict a patient’s course of disease is to compare the patient to a sibling carrying the same disease-causing variants. Sibling studies are a valuable tool both in evaluating genotype–phenotype correlations and in patient counseling and prognosis; however, research focused on inter-sibling concordance in STGD1 is limited. For a study published in Ophthalmology, we set out to investigate this inter-sibling concordance to facilitate patient prognosis and to investigate genotype-phenotype correlations.
We included siblings with a phenotype consistent with STGD1 seen at an outpatient clinic based on:
1) The availability of adequate clinical data.
2) At least one fundus autofluorescence (FAF) image of both eyes.
3) The presence of at least two likely disease-causing variants in the ABCA4 gene.
Patients were compared relative to disease duration in order to correct for phenotypic differences caused by large differences in age of disease onset. Age of onset was defined as the age at which the patient first experienced complaints.
We found that phenotypic discordance between siblings with STGD1 disease carrying the same ABCA4 variants is a prevalent phenomenon. While the FAF phenotypes are highly comparable between siblings, functional outcomes and age of onset differ substantially. These differences complicate both sibling-based prognosis and genotype–phenotype correlations and have important implications for patient care and management. Interestingly, these differences in phenotype were already present in very young children, when environmental factors are less important modifiers.
Our results are difficult to reconcile with the suggested simple inheritance of STGD1 and indicate that other, yet-unidentified environmental and/or genetic factors modify the disease course. Further research into genotype–phenotype correlations and in determining disease-modifying factors are paramount in unravelling this complex disease.