North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene

abstract: ...Purpose To identify the underlying cause of disease in a large family with North Carolina macular dystrophy (NCMD). Methods A large four-generation family (RFS355) with an autosomal dominant form of NCMD was ascertained. Family members underwent comprehensive visual function evaluations. Blood or saliva from six affected family members and three unaffected spouses 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 of the linkage region followed by next-generation sequencing (NGS). Standard PCR and dideoxy sequencing were used to further characterize the mutation. Results Of the 12 eyes examined in six affected individuals, all but two had Gass grade 3 macular degeneration features. Large central excavation of the retinal and choroid layers, referred to as a macular caldera, was seen in an age-independent manner in the grade 3 eyes. The calderas are unique to affected individuals with MCDR1. Genome-wide linkage mapping and haplotype analysis of markers from the chromosome 6q region were consistent with linkage to the MCDR1 locus. Whole exome sequencing and custom-capture NGS failed to reveal 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 on chromosome 6q. This region contains two genes, CCNC and PRDM13 . The duplication creates a partial copy of CCNC and a complete copy of PRDM13 . The duplication was found in all affected members of the family and is not present in any unaffected members. The duplication was not seen in 200 ethnically matched normal chromosomes. Conclusions The cause of disease in the original family with MCDR1 and several others has been recently reported to be dysregulation of the PRDM13 gene, caused by either single base substitutions in a DNase 1 hypersensitive site upstream of the CCNC and PRDM13 genes or a tandem duplication of the PRDM13 gene. The duplication found in the RFS355 family is distinct from the previously reported duplication and provides additional support that dysregulation of PRDM13 , not CCNC , is the cause of NCMD mapped to the MCDR1 locus.

...Mol Vis Mol. Vis MV Molecular Vision 1090-0535 Molecular Vision 27777503 5070570 99 2016MOLVIS0324 Research Article North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene Bowne Sara J. 1 Sullivan Lori S. 1 Wheaton Dianna K. 2 Locke Kirsten G. 2 Jones Kaylie D. 2 Koboldt Daniel C. 3 Fulton Robert S. 3 Wilson Richard K. 3 Blanton Susan H. 4 Birch David G. 2 5 Daiger Stephen P. 1 6 1 Human Genetics Center, School of Public Health, The University of Texas

... uncovered a tandem duplication of approximately 60 kb on chromosome 6q. This region contains two genes, CCNC and PRDM13 . The duplication creates a partial copy of CCNC and a complete copy of PRDM13 . The duplication was found in all affected members of the family and is not present in any unaffected members. The duplication was not seen in 200 ethnically matched normal chromosomes. Conclusions The cause of disease in the original family with MCDR1 and several others has been recently reported to be dysregulation of the PRDM13 gene, caused by either single base substitutions in a DNase 1 hypersensitive site upstream of the CCNC and PRDM13 genes or a tandem duplication of the PRDM13 gene. The duplication found in the RFS355 family is distinct from the previously reported duplication and provides additional support that dysregulation of PRDM13 , not CCNC , is the cause of NCMD mapped to the MCDR1 locus. GalleyStatus Export to XML Introduction Families with North Carolina macular dystrophy were first

... was identified using whole genome sequencing of individuals from two families mapped to the MCDR1 locus [ 9 ]. Sequence analysis identified a nucleotide substitution at chr6:100,040,906 G>T (hg19) that was subsequently found in nine families. In addition, a C>T substitution at chr6:100,041,040 was found in an additional family with NCMD. These two nucleotide substitutions are located in a DNase I hypersensitive site 5 of two genes, PR/SET domain-containing zinc finger protein 13 ( PRDM13 ; Gene ID 59336, OMIM 616741 ) and cyclin-C protein ( CCNC ; Gene ID 892, OMIM 123838 ). In addition to these two nucleotide substitutions, a third family was found to have a 123 kb duplication of a region that includes the PRDM13 gene and the DNase I hypersensitive site. Experiments using induced pluripotent stem cells (iPSCs) suggested that the disease was likely due to the dysregulation of PRDM13 [ 9 ]. This study describes the clinical characterization and mutation identification of another NCMD family, RFS355, which maps to the MCDR1 locus. The tandem duplication identified in this family is different from that reported by Small et al., further strengthening the premise that dysregulation of the PRDM13 gene, not the CCNC gene, is the cause of NCMD (MCDR1) [ 9 ]. Methods This study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board at each participating institution. Written informed consent was obtained from each participant before the examination and genetic

... duplication found of the CCNC gene is only from exons 1 through 9 making it unlikely that any protein is generated from the duplicated region. The presence of the entire PRDM13 gene downstream from the DNase hypersensitivity site likely causes a change in PRDM13 protein levels compared to wild-type levels. Results Six affected members of the RFS355 family underwent comprehensive clinical exams. Clinical data are presented in Table 1 . The six affected individuals were tested at several different ages

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Gene: PRDM13 - PR domain containing 13 - (NCBI)

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