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

Sara J. Bowne, Lori S. Sullivan, Dianna K. Wheaton, Kirsten G. Locke, Kaylie D. Jones, Daniel C. Koboldt, Robert S. Fulton, Richard K. Wilson, Susan H Blanton, David G. Birch, Stephen P. Daiger

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1239-1247
Number of pages9
JournalMolecular Vision
Volume22
StatePublished - Oct 17 2016

Fingerprint

Gene Duplication
Exome
Chromosomes
Spouses
Genes
Choroid
Deoxyribonucleases
Macular dystrophy, retinal, 1, North Carolina type
Chromosome Mapping
Macular Degeneration
Genetic Markers
Saliva
Haplotypes
Genome
Phenotype
Polymerase Chain Reaction
Mutation
DNA

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Bowne, S. J., Sullivan, L. S., Wheaton, D. K., Locke, K. G., Jones, K. D., Koboldt, D. C., ... Daiger, S. P. (2016). North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene. Molecular Vision, 22, 1239-1247.

North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene. / Bowne, Sara J.; Sullivan, Lori S.; Wheaton, Dianna K.; Locke, Kirsten G.; Jones, Kaylie D.; Koboldt, Daniel C.; Fulton, Robert S.; Wilson, Richard K.; Blanton, Susan H; Birch, David G.; Daiger, Stephen P.

In: Molecular Vision, Vol. 22, 17.10.2016, p. 1239-1247.

Research output: Contribution to journalArticle

Bowne, SJ, Sullivan, LS, Wheaton, DK, Locke, KG, Jones, KD, Koboldt, DC, Fulton, RS, Wilson, RK, Blanton, SH, Birch, DG & Daiger, SP 2016, 'North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene', Molecular Vision, vol. 22, pp. 1239-1247.
Bowne SJ, Sullivan LS, Wheaton DK, Locke KG, Jones KD, Koboldt DC et al. North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene. Molecular Vision. 2016 Oct 17;22:1239-1247.
Bowne, Sara J. ; Sullivan, Lori S. ; Wheaton, Dianna K. ; Locke, Kirsten G. ; Jones, Kaylie D. ; Koboldt, Daniel C. ; Fulton, Robert S. ; Wilson, Richard K. ; Blanton, Susan H ; Birch, David G. ; Daiger, Stephen P. / North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene. In: Molecular Vision. 2016 ; Vol. 22. pp. 1239-1247.
@article{abe1a2269dd048dabcbec3bb3dcb6f04,
title = "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.",
author = "Bowne, {Sara J.} and Sullivan, {Lori S.} and Wheaton, {Dianna K.} and Locke, {Kirsten G.} and Jones, {Kaylie D.} and Koboldt, {Daniel C.} and Fulton, {Robert S.} and Wilson, {Richard K.} and Blanton, {Susan H} and Birch, {David G.} and Daiger, {Stephen P.}",
year = "2016",
month = "10",
day = "17",
language = "English (US)",
volume = "22",
pages = "1239--1247",
journal = "Molecular Vision",
issn = "1090-0535",

}

TY - JOUR

T1 - North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene

AU - Bowne, Sara J.

AU - Sullivan, Lori S.

AU - Wheaton, Dianna K.

AU - Locke, Kirsten G.

AU - Jones, Kaylie D.

AU - Koboldt, Daniel C.

AU - Fulton, Robert S.

AU - Wilson, Richard K.

AU - Blanton, Susan H

AU - Birch, David G.

AU - Daiger, Stephen P.

PY - 2016/10/17

Y1 - 2016/10/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85008195110&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85008195110&partnerID=8YFLogxK

M3 - Article

VL - 22

SP - 1239

EP - 1247

JO - Molecular Vision

JF - Molecular Vision

SN - 1090-0535

ER -