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Kent W Small, Edwin M Stone, Monique J Leys, Richard Alan Lewis, Steven Agemy, Charles A Garcia, Todd Schneiderman, Thomas A Rice, Fadi Shaya; North Carolina Macular Dystrophy (NCMD/MCDR1): Haplotype analysis shows single ancestral founder in 13 American families. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4462.
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© ARVO (1962-2015); The Authors (2016-present)
North Carolina Macular Dystrophy (NCMD / MCDR1) is an autosomal dominant congenital developmental disorder of the macula with highly variable expressivity. Small et al mapped NCMD by linkage in 1991 to chromosome 6q16 in the original single large family from North Carolina and found the first 5 mutations in 2016. The first mutation found was a single base pair change (Chr 6: 99593030 G>T, Hg38) in a non-coding region of a DNASE1 site (designated “V1”) presumably affecting the expression of PRDM13. Subsequently, Small et al. have found over 40 families with the NCMD phenotype, 13 of which have the V1 mutation. Because all of these 13 are American, we suspected that there may be a single common founder despite no known genealogical connections among them.
We performed haplotype analyses of these 13 American NCMD families. If these 13 families have a common founder for NCMD then a shared region of DNA on chromosome 6q16 should be evident. Genotyping of the 13 NCMD families with V1 mutations was performed using 11 polymorphic short tandem repeats (STRs) within the 4,528,000 bp region centered on the MCDR1 / PRDM13 region. Four of the STR polymorphic markers were newly developed by our lab specifically to study this genomic region in these families. The computer program, Progeny, was utilized to construct the haplotypes from the raw genotype data.
All 13 families showed overwhelming evidence of a common shared genomic haplotype for all 11 STR markers for the MCDR1 region on chromosome 6q16.This is apparently a unique haplotype for American NCMD patients as no such evidence was found in the other NCMD families with the other NCMD mutation. Twelve of the 13 families are Caucasian and one is African American.
The shared haplotype in these 13 families indicates that there is a single common founder for NCMD in the United States. None of these 13 American families have any known genealogical relationship with each other. The V1 mutation and this haplotype have only been found in Americans while the V2 mutation has been found in Europeans and some Americans. Currently there are a total of 9 distinct mutations causing NCMD and each one seems to be a new unique mutation. Three are point mutations in non-coding regions in the MCDR1 locus and remainder are duplications in the MCDR1 and MCDR3 loci.
This is a 2020 ARVO Annual Meeting abstract.
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