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N. L. Parmalee, K. Kiryluk, C. Schubert, K. Allikmets, M. Gillies, R. Allikmets, The MacTel Project; Determining the Genetic Cause of Macular Telangiectasia. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1656.
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Macular Telangiectasia (MacTel) is a rare retinal macular disease causing loss of central visual acuity between the 3rd and 5th decades of life. The disease is characterized by changes in autofluorescence in the macula, macular pigment abnormalities, and telangiectatic blood vessels in the retina. Most described cases are sporadic; however, recently many familial cases were indentified suggesting a genetic component. Affected individuals, their family members, and unaffected controls are being recruited at 26 centers in 7 countries within the MacTel Project. The current cohort available for genetic analyses includes 332 unrelated affected individuals and 240 family members.
We performed genome-wide linkage analysis in 20 families (72 individuals) where two or more family members were diagnosed with the disease. DNA samples were genotyped on the Illumina 1M Duo chip. Parametric and nonparametric linkage analyses were carried out in MERLIN. Candidate genes for MacTel were selected based on functional hypotheses; 26 genes involved in retinal angiogenesis, macular pigment transport, and phenotypes similar to MacTel were screened by direct sequencing in probands of 8 families. Identified variants were analyzed for segregation or association with the disease using Illumina SNP chip data, direct sequencing and Taqman assays.
Three suggestive peaks were identified by linkage analysis on chromosomes 7, 10, and 12. The peaks on chromosomes 7 and 12 are driven by one large family, which also contributes to the peak on chromosome 10; all other families contribute to the peak on chromosome 10. No disease-causing mutations have been identified in candidate genes to date; however, several SNPs are being investigated for a possible disease-modifying effect.
To determine the causal gene(s) for MacTel, suggestive linkage peaks are being evaluated in detail by haplotype analyses. Additional follow-up studies include association analyses of disease-modifying variants in candidate genes and whole exome sequencing in selected multiplex families.
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