title: North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of thePRDM13gene.
abstract: To identify the underlying cause of disease in a large family with North Carolina macular dystrophy (NCMD).
  
  
  
  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.
  
  
  
  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,CCNCandPRDM13. The duplication creates a partial copy ofCCNCand a complete copy ofPRDM13. 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.
  
  
  
  The cause of disease in the original family with MCDR1 and several others has been recently reported to be dysregulation of thePRDM13gene, caused by either single base substitutions in a DNase 1 hypersensitive site upstream of theCCNCandPRDM13genes or a tandem duplication of thePRDM13gene. The duplication found in the RFS355 family is distinct from the previously reported duplication and provides additional support that dysregulation ofPRDM13, notCCNC, is the cause of NCMD mapped to the MCDR1 locus.
authors: Human Genetics Center, School of Public Health, The University of Texas Health Science Center (UTHealth), Houston, TX.
authors: Sara J
authors: SJ
authors: Bowne
authors: Human Genetics Center, School of Public Health, The University of Texas Health Science Center (UTHealth), Houston, TX.
authors: Lori S
authors: LS
authors: Sullivan
authors: Retina Foundation of the Southwest, Dallas, TX.
authors: Dianna K
authors: DK
authors: Wheaton
authors: Retina Foundation of the Southwest, Dallas, TX.
authors: Kirsten G
authors: KG
authors: Locke
authors: Retina Foundation of the Southwest, Dallas, TX.
authors: Kaylie D
authors: KD
authors: Jones
authors: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO.
authors: Daniel C
authors: DC
authors: Koboldt
authors: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO.
authors: Robert S
authors: RS
authors: Fulton
authors: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO.
authors: Richard K
authors: RK
authors: Wilson
authors: Dr. John T. Macdonald Foundation Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami, Miami, FL.
authors: Susan H
authors: SH
authors: Blanton
authors: Retina Foundation of the Southwest, Dallas, TX; Dept. of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX.
authors: David G
authors: DG
authors: Birch
authors: Human Genetics Center, School of Public Health, The University of Texas Health Science Center (UTHealth), Houston, TX; Ruiz Dept. of Ophthalmology, University of Texas Health Science Center Houston (UTHealth), Houston, TX.
authors: Stephen P
authors: SP
authors: Daiger
mesh_terms: D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D003317:Corneal Dystrophies, Hereditary / Q000175:diagnosis / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D020080:Tandem Repeat Sequences / Q000235:genetics*; D041623:Tomography, Optical Coherence; D014157:Transcription Factors / Q000235:genetics*; D014792:Visual Acuity / Q000502:physiology
chemical_list: D005136:Eye Proteins; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase