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Eileen Hwang, Denise Morgan, James L Zimmerman, Claude F Burgoyne, Paul S Bernstein, Margaret M DeAngelis; An Alu-mediated copy number variation mediates progressive optic nerve cupping in autosomal dominant optic pit. Invest. Ophthalmol. Vis. Sci. 2017;58(8):576.
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Progressive optic nerve cupping was previously described in a Midwestern family with autosomal dominant optic pit, i.e. “cavitary optic disc anomaly.” Affected members of the Midwestern family were found to have two extra copies (four copies total) of a region upstream from the MMP19 gene (Hazlewood, 2015). We describe a second family with a similar but independent copy number variation.
Members of a three-generation Utah pedigree were characterized by clinical exam, fundus photography, and optical coherence tomography to determine disease status. Leukocyte DNA from 16 individuals was analyzed using two independent TaqMan copy number variation assays located in the region previously described in the Midwestern family.
All four affected individuals in the Utah family had one extra copy (three copies total) of the non-coding region upstream of MMP19. The 13 unaffected individuals had two copies of the region, which is the normal genotype. In three of the four affected individuals, long term follow up with optic nerve photos demonstrated progressive cupping of the optic nerve head.
We are the second group to describe a family with autosomal dominant optic pit associated with a copy number variation in the non-coding region upstream of MMP19. Affected members of the Midwestern family had two extra copies of the region, whereas affected members of the Utah family had one extra copy. The description of an independent family with a different variation in the same region confirms the role of this locus in disease pathogenesis. Studies are ongoing to investigate possible phenotypic differences from the previously described family.Reference: Hazlewood et al. (2015) Heterozygous Triplication of Upstream Regulatory Sequences Leads to Dysregulation of Matrix Metalloproteinase 19 in Patients with Cavitary Optic Disc Anomaly. Human Mutation. 36:369-378.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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