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AUTOSOMAL RECESSIVE VITELLIFORM MACULAR DYSTROPHY IN A LARGE COHORT OF VITELLIFORM MACULAR DYSTROPHY PATIENTS

Kinnick, Tyson R PhD*; Mullins, Robert F PhD*; Dev, Sundeep MD; Leys, Monique MD; Mackey, David A MD§; Kay, Christine N MD*; Lam, Byron L MD; Fishman, Gerald A MD**; Traboulsi, Elias MD††; Iezzi, Raymond MD‡‡; Stone, Edwin M MD, PhD§§

doi: 10.1097/IAE.0b013e318203ee60
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Purpose: To report 11 cases of autosomal recessive vitelliform macular dystrophy and to compare their molecular findings and phenotypic characteristics with those of patients with the more common and well-described dominant form of the disease.

Methods: Blood samples were obtained from 435 unrelated individuals with a clinical diagnosis of vitelliform macular dystrophy and screened for mutations in the coding sequences of BEST1. Medical records and retinal photographs of selected patients were reviewed.

Results: Nine of the 435 probands were found to have 2 plausible disease-causing variations in BEST1, while 198 individuals were found to have heterozygous variations compatible with autosomal dominant inheritance. Inheritance phase was determined in three of the recessive families. Six novel disease-causing mutations were identified among these recessive patients: Arg47Cys, IVS7−2A>G, IVS7+4G>A, Ile205del12ATCCTGCTCCAGAG, Pro274Arg, and Ile366delCAGGTGTGGC. Forty-four novel disease-causing mutations were identified among the patients with presumed autosomal dominant disease. The phenotype of patients with recessive alleles for BEST1 ranged from typical vitelliform lesions to extensive extramacular deposits.

Conclusion: The authors provide evidence that two abnormal BEST1 alleles, neither of which causes macular disease alone, can act in concert to cause early-onset vitelliform macular dystrophy.

Supplemental digital content is available in this text. Vitelliform macular dystrophy is classically inherited as an autosomal dominant monogenetic disease of the macula. In this article, we review the molecular genetic studies of a cohort of 435 patients with vitelliform macular dystrophy, including 9 with recessive inheritance, and explore certain differences between dominant and recessive phenotypes.

From the *Department of Ophthalmology and Visual Sciences, Carver Family Center for Macular Degeneration, University of Iowa, Iowa City, Iowa; †Vitreoretinal Surgery, Minneapolis, Minnesota; ‡Department of Ophthalmology, West Virginia University, Morgantown, West Virginia; §Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Western Australia, Australia; ¶Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida; **Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois; ††Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio; ‡‡Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota; and §§Howard Hughes Medical Institute, Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Carver Family Center for Macular Degeneration, University of Iowa, Iowa City, Iowa.

Supported by an unrestricted challenge grant from the Research to Prevent Blindness (to West Virginia University), the Department of Defense (W81XWH-09-1-0674 to B.L.L.), the National Eye Institute (EY017451 to R.F.M. and EY016822 to E.M.S.), the Hansjoerg EJW Kolder Professorship in Best Disease Research (to R.F.M.), the Foundation Fighting Blindness, the Carver Endowment for Molecular Ophthalmology, the Carver Family Center for Macular Degeneration, and the Howard Hughes Medical Institute.

The authors have no proprietary or conflict of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.retinajournal.com).

Reprint requests: Edwin M. Stone, MD, PhD, Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Carver Family Center for Macular Degeneration, 375 Newton Road, 4111 MERF, Iowa City, IA 52242; e-mail: edwin-stone@uiowa.edu

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