Genomewide homozygosity mapping and molecular analysis of a candidate gene located on 22q13 (fibulin-1) in a previously undescribed vitreoretinal dystrophy

OBJECTIVES To localize the gene that causes an autosomal recessively inherited vitreoretinal dystrophy that has not been described, to our knowledge, and to analyze a candidate gene mapped to 22q13 (fibulin-1 [FBLN1]). METHODS Homozygosity mapping with 500 microsatellite markers spread over the whole genome (mean distance, 7.2 centimorgans [cM]) and mutation analysis of the complete coding region of FBLN1. RESULTS Homozygosity for all analyzed markers was found in the 4 affected siblings in a region on chromosome 22 encompassing 12 cM from D22S444 (centromeric) to D22S1170 (telomeric). Lod scores were between 0.017 and 2.36 (theta = 0). A mutation analysis of the complete coding region of FBLN1, which encodes interacting extracellular matrix proteins, revealed 4 previously undescribed single nucleotide polymorphisms. CONCLUSIONS A genomewide homozygosity mapping analysis supported the hypothesis that the gene responsible for a unique vitreoretinal dystrophy is located on chromosome 22q13. No obviously pathogenic mutation was found in the candidate gene, FBLN1

Genetic Linkage of Wagner Disease and Erosive Vitreoretinopathy to Chromosome 5q13-14

Background: Wagner disease and erosive vitreoretinopathy are potentially blinding autosomal dominant diseases that share some similarities with Stickler syndrome. However, both disorders have associated retinal pigment epithelial changes, poor night vision, visual field defects, and abnormal electroretinographic findings, which are not found in families with COL2A1-associated Stickler syndrome. In addition, rhegmatogenous retinal detachments are uncommon in Wagner disease but occur in approximately 50% of patients with either Stickler syndrome or erosive vitreoretinopathy. Objectives: To identify the chromosomal location of the genes involved in Wagner disease and erosive vitreoretinopathy and to distinguish these conditions genetically from Stickler syndrome. Methods: Fifteen affected members of a family affected with erosive vitreoretinopathy and 24 affected descendants of the pedigree described by Wagner were genotyped with a set of short tandem repeat polymorphisms distributed across the genome. Results: Significant linkage was observed in each family between the disease phenotype and markers that map to chromosome 5q13-14. The highest lod score for the family affected with erosive vitreoretinopathy was 4.2 and was obtained with marker GATA3H06 (theta = 0). The highest lod score for the family affected with Wagner disease was 5.8 and was obtained with marker D5S815 (theta = 0). A candidate gene (cartilage link protein) that is known to lie near the linked interval was screened for mutations, but none was found in either family. Conclusions: These data suggest that erosive vitreoretinopathy and Wagner disease are allelic disorders and demonstrate that they are genetically distinct from COL2A1-associated Stickler syndrome