A tandem duplication of PRDM13 in a family with North Carolina Macular Dystrophy (MCRD1)

Abstract

Purpose : Purpose: To identify the underlying cause of disease in a large family with North Carolina Macular Dystrophy

Methods : Methods: A large four-generation family (RFS355) with an autosomal dominant form of North Carolina Macular Dystrophy was ascertained. Family members underwent comprehensive visual function evaluations. Blood from six affected family members was collected and DNA tested for linkage to the MCDR1 locus on chromosome 6q12. Three affected family members and two unaffected spouses underwent whole exome sequencing (WES) and subsequently custom capture next generation sequencing (NGS) of the entire linkage region.

Results : Results: Each of the six affected family members presented with Grade 3 macular degeneration in at least one eye. Large central excavation of the retinal and choroid layers, referred to as macular caldera, was seen in an age-independent manner in ten eyes. Haplotype analysis of markers from the chromosome 6 linkage region was consistent with linkage to the MCDR1 locus. Neither WES nor the custom capture NGS revealed any rare coding variants segregating with the phenotype. Analysis of the custom capture NGS sequencing data for copy number variants uncovered a tandem duplication of approximately 60 kb, in a region containing two genes – CCNC and PRDM13. The duplication creates a partial copy of CCNC and a complete copy of PRDM13 and is found in all affected members of the family. The duplication was not seen in 200 ethnically matched normal chromosomes.

Conclusions : Conclusions: The cause of disease in the original MCDR1 family and several others has been recently reported to be the dysregulation of the PRDM13 gene, caused by either single base substitutions in a DNase 1 hypersensitive site upstream of the gene or by duplication of the entire gene (Small et al., 2015). The duplication found in the RFS355 family, which is distinct from the previously reported duplication, provides support for that model and may provide additional insight into the mechanism of disease.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.