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Terri Lois Young, Stuart W Tompson, Kristina N Whisenhunt, Quintin DeGroot, Krystina Quow, Xiaoyan Luo, Natalie A Afshari; Hereditary Benign Intraepithelial Dykeratosis in a Native American Tribe. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1016.
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© ARVO (1962-2015); The Authors (2016-present)
Autosomal dominant hereditary benign intraepithelial dyskeratosis (HBID) is a rare syndrome of variable ocular surface irritation with overgrowth and leukoplakia of the conjunctiva and cornea, and occasional accompanying oral mucosal keratosis. Reported cases are primarily from a large tri-ethnic North Carolina Haliwa-Saponi Native American tribe isolate, although a novel gene- NLRP1- has been identified in a Caucasian French family. The chromosome 4q35 disease locus was determined by microsatellite linkage analysis in 2 families within the tribal population. Two of the linked markers displayed tri-allelism in all 25 affected individuals of 55 subjects studied, suggesting that a duplication of this genomic region was causal. We independently ascertained HBID families from the same isolate, and performed repeat linkage analysis with denser coverage to confirm linkage, and to delimit the genomic interval in which the true causal variant might reside.
Three families (9 affected/ 4 unaffected) were ascertained, and participant DNA was used for study. We designed and analyzed 25 FAM tagged fluorescent microsatellite markers from the telomeric 4q35 locus to the centromere for over 122Mb. After standard PCR and fragment analysis, the samples were interpreted by Peak Scanner (ABI). Sanger sequencing of tribal member DNA samples was performed of the coding and intron-exon boundary regions of the NLRP1 gene.
We confirmed the presence of tri-allelism at markers D4S1652 and D4S2390 in 6 affected individuals. This was also identified in 3 unaffected individuals, thereby excluding this genomic variant as disease causing. No pathogenic variants of NLRP1 were determined for affected tribal members.
Our analysis did not identify a haplotype common to all affected individuals, effectively excluding the q-arm of chromosome 4 as the locus for HBID. The HBID phenotype displays genetic heterogeneity. To delineate the causal genotype/variant, exome sequencing of tribal members is underway.
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