Genotype-phenotype correlations in Stargardt disease highlight considerable complexity

Researchers at Radboud University Medical Center, Nijmegen, the Netherlands, have reported that phenotypic divergence between siblings with Stargardt disease (STGD1) carrying the same ABCA4 gene variants underscores the complexity of clinical management. The researchers have identified that fundus autofluorescence phenotypes can be highly comparable between siblings, while functional outcomes can differ substantially. According to the study results, “this complicates both sibling-based prognosis and genotype-phenotype correlations, and has important implications for patient care and management”.  Designing clinical trials for patients with differing baselines and differing disease course will be challenging.

 

Stargardt disease is an autosomal recessive retinal dystrophy with a prevalence of about 1/10,000 and therefore it is estimated that there are 500,000 patients with the disorder worldwide.  The clinical phenotype for the disease varies widely from mild visual complaints up to 50 years age or more, to severe visual impairment occurring at a young adolescence age with advanced retinal degeneration.  There is not sufficient data to understand the correlations between genotype and phenotype for the ABC4A gene, along with the additional genetic modifiers and environmental components that can alter the course of the disease. Researchers have previously reported that over 900 unique variants have been identified in ABCA4-related retinopathies and 50% of the variants are among missense mutations.

 

In terms of the specific results, there have been substantial differences in age of onset among 5/17 families, ranging from 13 to 39 years. The median BCVA at baseline was 0.60 (range -0.20 – 2.30) LogMAR (20/80 (range 20/12 – hand movement (HM)) Snellen) in the right, and 0.50 (range -0.20 – 2.30) LogMAR (20/63 (20/12 – HM) Snellen) in the left eye. Disease duration-matched BCVA was investigated in 12/17 families and the median difference was 0.41 (0.00 – 1.10) LogMAR for the right and 0.41 (0.00 – 1.08) LogMAR for the left eye. In addition, the researchers observed notable differences in time to develop severe visual impairment in seven families, ranging from 1 to 29 years. Median central retinal atrophy 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. Similarly, qualitative fundus autofluorescence and SD-OCT phenotypes were highly comparable between siblings.  Clearly, when identifying the specific ABCA4 gene variants shown, there appears to be other factors that determine the course of a genetic disease and this information is not yet known.  therefore there is a significant amount of research to be done.  Commenting in the report, the researchers have stated that the studies “have found significant differences in functional visual outcomes (BCVA, time to develop SVI, age of onset) and DDAF (definitely decreased autofluorescence) area between siblings with STGD1 in 11 out of 17 families despite carrying the same ABCA4 variants and having highly comparable FAF (fundus autofluorescence) phenotypes. These findings can potentially be explained by the presence of currently unidentified environmental and genetic modifying factors that further complicate sibling-based prognosis”.

401 thoughts on “Genotype-phenotype correlations in Stargardt disease highlight considerable complexity”

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  186. When I initially commented I appear to have clicked the -Notify me when new comments are added- checkbox and now every time a comment is added I get four emails with the exact same comment. Perhaps there is a means you are able to remove me from that service? Cheers!

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  191. Hello there! I could have sworn I’ve been to your blog before but after going through some of the articles I realized it’s new to me. Anyways, I’m certainly happy I came across it and I’ll be book-marking it and checking back frequently!

  192. You are so awesome! I don’t believe I’ve read through a single thing like this before. So wonderful to find somebody with original thoughts on this subject. Really.. thank you for starting this up. This web site is something that is needed on the internet, someone with some originality!

  193. When I originally left a comment I seem to have clicked on the -Notify me
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  194. When I initially commented I clicked the -Notify me when new comments are added- checkbox and also now each time a comment is added I obtain 4 e-mails with the same remark. Exists any way you can remove me from that solution? Thanks!

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