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Clinical and genetic characterization of a Danish family with North Carolina macular dystrophy.

ABSTRACT: To describe the phenotype of a family with an autosomal dominant macular dystrophy and identify the chromosomal location of the gene that causes this phenotype.Twelve members of a three-generation family underwent routine clinical examination, including fundus photography. Four of the patients underwent extended examination with Goldmann perimetry, full-field electroretinogram, dark adaptation, and color vision testing, and two patients underwent optical coherence tomography and fundus autofluorescence examination. DNA samples were obtained from 12 family members and 3 spouses and genotyped at the known North Carolina Macular Dystrophy (NCMD) locus on chromosome 6q (MCDR1: OMIM 136550) using short tandem repeat polymorphisms. DNA samples were subsequently examined with a genome-wide scan of single nucleotide polymorphisms and the genotypes that were produced were studied with linkage and haplotype analyses.The 10 affected family members had clinical findings of macular lesions that are typical for NCMD. The small drusen-like yellowish lesions of mild NCMD were hyperautofluorescent. Hyperpigmented foveal lesions were surrounded by a zone of confluent hyperautofluorescence. Linkage analysis of short tandem repeat polymorphism genetic markers excluded the NCMD locus on chromosome 6. However, analysis of single nucleotide polymorphism genotypes from a genome-wide scan showed that NCMD in our pedigree is linked to a region on chromosome 5p that overlaps the previously mapped macular dystrophy (MCDR3) locus with a maximum log of the odds (LOD) score of 2.69 at a recombination fraction of 0.00 (markers D5S406, D5S1987, and D5S2505).We report the first pedigree with NCMD from Scandinavia, and the first confirmation that a gene for this condition is located on chromosome 5p13-p15. The bright elements or lesions typical of NCMD differed from drusen in that no sign of accumulation of material between the retinal pigment epithelium and Bruch's membrane was seen. While the present study has found indications that the elements are located in the outermost layers of the retina, their precise location remains to be identified directly.

SUBMITTER: Rosenberg T

PROVIDER: S-EPMC3002954 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Clinical and genetic characterization of a Danish family with North Carolina macular dystrophy.

Rosenberg Thomas T Roos Ben B Johnsen Thorkild T Bech Niels N Scheetz Todd E TE Larsen Michael M Stone Edwin M EM Fingert John H JH

Molecular vision 20101209

<h4>Purpose</h4>To describe the phenotype of a family with an autosomal dominant macular dystrophy and identify the chromosomal location of the gene that causes this phenotype.<h4>Methods</h4>Twelve members of a three-generation family underwent routine clinical examination, including fundus photography. Four of the patients underwent extended examination with Goldmann perimetry, full-field electroretinogram, dark adaptation, and color vision testing, and two patients underwent optical coherence ...[more]

PMID: 21179233

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Project description:PurposeTo identify specific mutations causing North Carolina macular dystrophy (NCMD).DesignWhole-genome sequencing coupled with reverse transcription polymerase chain reaction (RT-PCR) analysis of gene expression in human retinal cells.ParticipantsA total of 141 members of 12 families with NCMD and 261 unrelated control individuals.MethodsGenome sequencing was performed on 8 affected individuals from 3 families affected with chromosome 6-linked NCMD (MCDR1) and 2 individuals affected with chromosome 5-linked NCMD (MCDR3). Variants observed in the MCDR1 locus with frequencies <1% in published databases were confirmed using Sanger sequencing. Confirmed variants absent from all published databases were sought in 8 additional MCDR1 families and 261 controls. The RT-PCR analysis of selected genes was performed in stem cell-derived human retinal cells.Main outcome measuresCo-segregation of rare genetic variants with disease phenotype.ResultsFive sequenced individuals with MCDR1-linked NCMD shared a haplotype of 14 rare variants spanning 1 Mb of the disease-causing allele. One of these variants (V1) was absent from all published databases and all 261 controls, but was found in 5 additional NCMD kindreds. This variant lies in a DNase 1 hypersensitivity site (DHS) upstream of both the PRDM13 and CCNC genes. Sanger sequencing of 1 kb centered on V1 was performed in the remaining 4 NCMD probands, and 2 additional novel single nucleotide variants (V2 in 3 families and V3 in 1 family) were identified in the DHS within 134 bp of the location of V1. A complete duplication of the PRDM13 gene was also discovered in a single family (V4). The RT-PCR analysis of PRDM13 expression in developing retinal cells revealed marked developmental regulation. Next-generation sequencing of 2 individuals with MCDR3-linked NCMD revealed a 900-kb duplication that included the entire IRX1 gene (V5). The 5 mutations V1 to V5 segregated perfectly in the 102 affected and 39 unaffected members of the 12 NCMD families.ConclusionsWe identified 5 rare mutations, each capable of arresting human macular development. Four of these strongly implicate the involvement of PRDM13 in macular development, whereas the pathophysiologic mechanism of the fifth remains unknown but may involve the developmental dysregulation of IRX1.

Project description: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, 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.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.

Dataset Information

Clinical and genetic characterization of a Danish family with North Carolina macular dystrophy.

Publications

Clinical and genetic characterization of a Danish family with North Carolina macular dystrophy.

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