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Terri L. Young, Khanh -Nhat Tran Viet, Diana Abbott, Ravikanth Metlapally, Erica Burner, Yi-Ju Li, Charles Johnson, Max R. Johnson; Novel Genetic Mapping in Wagner Syndrome. Invest. Ophthalmol. Vis. Sci. 2011;52(14):71.
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© ARVO (1962-2015); The Authors (2016-present)
Wagner syndrome (WS) (OMIM 143200) is an autosomal dominant (AD) vitreoretinopathy characterized by vitreous fibrillary condensations, lattice degeneration and high myopia, with a predisposition to develop cataracts and retinal detachments. WS maps to chromosome 5q13-14 with reported mutations in the CSPG2 gene. We studied a large three-generation Caucasian family with presumed WS. No CSPG2 sequence variations were identified. A whole genome linkage study was performed to identify a novel gene locus.
Linkage mapping of genomic DNA from 38 family members (9 affected) was performed using the Illumina Infinium HumanLinkage-24 Panel (5913 SNPs). Genotype data were checked for Mendelian inconsistencies. Affected-only AD and AR linkage models were run using FASTLINK/HOMOG and MERLIN for two-point and multipoint analyses, respectively. Multipoint linkage was analyzed by MERLIN using two sub-pedigrees. Full pedigree multipoint analysis for suggestive linkage regions (LOD >1.5) was performed using SIMWALK. Sequencing was conducted for the CSPG2 and Col2A1 genes. Primers covered all exons and intron/exon boundaries. Amplicons were sequenced to check for affected individual segregation. No variants followed segregation with the phenotype.
AD model parametric multipoint analysis demonstrated HLOD scores > 2.00 at chromosomes 1p36.11-1p36.13 ( rs4237), and 12q12-12q14.1 with a peak HLOD score of 2.27 (rs1107654). Multipoint analysis with SIMWALK replicated the 12q peak (peak LOD = 1.975). FASTLINK two-point analysis demonstrated several clustered chromosome 12q SNPs with HLOD > 1.0, with a peak HLOD score of 1.23 at rs10875671. Parametric multipoint AR model analysis demonstrated HLOD scores of > 1.80 at chromosomal regions 7q21.3-7q31.1 (rs714438), 8p12-8p11.21 (rs1522845), 8q12.1-8q13.3 (rs884839), 9q21.31-9q22.2 (rs1359168), and 14q31.3-14q32.32 (rs942190). SIMWALK analysis of MERLIN multipoint results replicated all regions. Two-point linkage analysis confirmed the 9q and 14q regions.
We report a linkage peak at chromosomes 1p36 and 12q12-12q14.1 associated with vitreoretinopathy in an AD model. Novel loci at chromosomes 9q and 14q were determined using a recessive model. Chromosome 12q12-12q14.1 is a known locus of the COL2A1 gene associated with Stickler syndrome, but sequence-screening ruled out its implication with this phenotype. These results support a novel gene for Wagner syndrome.
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