June 2013
Volume 54, Issue 15
ARVO Annual Meeting Abstract  |   June 2013
Pairwise Genotype/Phenotype Comparison to Predict Severity of ABCA4 Mutations
Author Affiliations & Notes
  • Crandall Peeler
    Ophthalmology, University of Michigan, Ann Arbor, MI
  • Jillian Huang
    Ophthalmology, University of Michigan, Ann Arbor, MI
  • Sarwar Zahid
    Ophthalmology, University of Michigan, Ann Arbor, MI
  • Naheed Khan
    Ophthalmology, University of Michigan, Ann Arbor, MI
  • Kari Branham
    Ophthalmology, University of Michigan, Ann Arbor, MI
  • Kanishka Jayasundera
    Ophthalmology, University of Michigan, Ann Arbor, MI
  • John Heckenlively
    Ophthalmology, University of Michigan, Ann Arbor, MI
  • Footnotes
    Commercial Relationships Crandall Peeler, None; Jillian Huang, None; Sarwar Zahid, None; Naheed Khan, None; Kari Branham, Arctic DX (P); Kanishka Jayasundera, None; John Heckenlively, None
  • Footnotes
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Investigative Ophthalmology & Visual Science June 2013, Vol.54, 2835. doi:
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      Crandall Peeler, Jillian Huang, Sarwar Zahid, Naheed Khan, Kari Branham, Kanishka Jayasundera, John Heckenlively; Pairwise Genotype/Phenotype Comparison to Predict Severity of ABCA4 Mutations. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2835.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: Rates of progression and degree of severity vary widely among patients with a clinical diagnosis of Stargardt disease. We describe several genotypic patterns associated with a more severe clinical course.

Methods: A retrospective chart review was performed to identify patients with one or two mutations in ABCA4. Each patient was paired with another who was closest in age. Clinical data - logMAR visual acuity, Goldmann visual field area and scotoma size, and photopic and scotopic B-wave amplitudes - were compared and a point was assigned to the individual with the more severe phenotype in each of the 5 categories. Total accumulated points served as the “clinical severity score” for each member of the pair. Mutation type - nonsense, missense, or frameshift - and affected domain within the ABCA4 protein - nucleotide-binding (NBD), extracellular (ECD), membrane-spanning (MSD), hydrophobic (HD), or intron - associated with the “better” and “worse” clinical severity score were recorded.

Results: Twenty-three single and 21 dual mutations pairs (N=88) were analyzed. The average age difference between paired patients was 1.7 years. Among single mutation pairs, a consistently severe phenotype was noted in individuals with NBD mutations. Eight of 9 instances comparing a patient with a NBD mutation to one with a different mutation domain showed the NBD phenotype to be more severe, with the one exception occurring in comparison to a nonsense mutation. In dual-mutation pairs, a severe phenotype was seen in individuals with combination NBD/ECD mutations (worse in 7 of 9 instances, including 2 comparisons to NBD/NBD). Four of 5 cases comparing nonsense mutations to a different mutation type demonstrated a more severe clinical picture in the former, with the one exception seen when the nonsense mutation occurred late in the ABCA4 protein (MSD2).

Conclusions: Difficulty in predicting the clinical course of Stargardt disease remains a major obstacle in clinical trial design, complicating the selection of appropriately matched controls. With the promise of gene therapy, finding an accurate method of grouping patients into “mild” and “severe” disease categories has become even more important. Our data suggest that certain genotypic information may serve this purpose, as patients with single NBD mutations, a combination of NBD and ECD mutations, and nonsense mutations were consistently found to have a more severe clinical phenotype.

Keywords: 696 retinal degenerations: hereditary • 539 genetics • 660 proteins encoded by disease genes  

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