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T.L. Young, S. Nallasamy, P. Paluru, M. Devoto, N. Wasserman, J. Zhou; Novel Locus for High–Grade Myopia in a Hutterite Population on Chromosome 10q . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2297.
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© ARVO (1962-2015); The Authors (2016-present)
Myopia is a common complex disorder, and severe forms have implications for blindness due to increased risk of premature cataracts, glaucoma, retinal detachment, and macular choroidal neovascularization. To date, autosomal dominant (AD) non–syndromic high–grade myopia (myopic spherical refractive error of ≤ 5.00 diopters) has been mapped to chromosomes 18p11.31, 12q21–23, 17q21–23, 7q36, and 2q37.1. Herein, we demonstrate linkage for AD non–syndromic high–grade myopia in a large Hutterite family to a locus on chromosome 10q21.1.
After clinical evaluation, genomic DNA was genotyped from 29 members of a Hutterite family from South Dakota (7 affected). The average refractive error of affected individuals was –7.04 diopters. Linkage was first excluded for the known AD non–syndromic high–grade myopia loci mentioned above using intra–interval and flanking microsatellite markers. Similarly, linkage was excluded for syndromic high myopia loci, including Stickler syndrome types 1, 2, and 3; Marfan syndrome; Ehlers–Danlos syndrome type 4; and juvenile glaucoma. A whole genome screen was then performed using 382 markers with an average inter–marker distance of 10 cM. Fine–point mapping was performed with additional microsatellite markers in all regions of the genome that gave positive LOD scores > 1.00. SimWalk2 software was used for multipoint and two–point linkage based on AD and recessive models with a 90% penetrance and a disease allele frequency of 0.001.
A maximum multipoint LOD score of 3.22 was achieved with an AD model at microsatellite marker D10S1643. Fine–point mapping and haplotype analysis defined a critical region of 2.67 cM on chromosome 10q21.1. Haplotype analysis demonstrated two distinct haplotypes segregating with high myopia, possibly indicative of two distinct mutations occurring in the same gene. A search for genes which physically map within this interval revealed only two known genes: PCDH15 (protocadherin 15) and ZWINT (ZW10 interactor). Mutational base pair screening of these genes resulted in 23 polymorphisms. None segregated with the affection status.
A novel high–grade myopia locus has been identified in a genetically isolated population, further demonstrating the genetic heterogeneity of this disorder.
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