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Andrea L Vincent, Lin Hou, Fadi Shaya, Monique J Leys, Kent W Small; Genetic characterisation of North Carolina Macular Dystrophy in a predominantly Non-Caucasian population. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1437.
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The causative genetic mechanism underlying North Carolina Macular Dystrophy (NCMD) is recently attributed to 3 non-coding mutations in an upstream regulatory region, the DNase1 hypersensitivity region (DHS) of a developmental gene, PRDM13 in the MCDR1 locus, as well as duplications involving PRDM13, and IRX1 at the MCDR3 locus. We aim to determine the underlying genetic cause for disease in a predominantly non-Caucasian cohort of patients with NCMD.
Ten probands (including 5 families) were identified from the New Zealand Database of Inherited Retinal Disease and the Macula & Retina Institute, USA, with probable NCMD, and demonstrating the phenotypic spectrum of disease. Sanger sequencing of the DNase1 hypersensitivity region and entire coding region of the PRDM13 gene was undertaken, including duplication detection using published primers. Subsequently, in 5 non-Caucasian probands, whole genome sequencing (WGS), and bioinformatics filtering in linked regions of chromosome 5 and 6 was performed, with segregation analysis in family members where possible.
In two Caucasian families, (NZ7 and 778 West Va), the previously described V2 variant in the DNase 1 hypersensitivity region was present. No other pathogenic variants were present in the DHS or coding exons of PRDM13 in the remaining probands. WGS in 3 probands (NZ Māori, Cambodian, Sri Lankan) revealed 3 unique variants in the region of the DNAse 1 hypersensitivity region, which are absent in databases of human variation, and segregate with disease in the Cambodian family. No duplications were present.
Recurrent mutations to date in the MCDR1 locus described in Caucasian probands were present in 2 families, both Caucasian, with a further 3 novel and rare variants of unknown significance identified close to the DNase1 region in non-Caucasian probands. No variant was detected in the remainder of probands. Further functional studies are necessary to determine the pathogenicity of these variants. The absence of known genetic mechanisms suggests genetic diversity for NCMD in the non-Caucasian population.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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