AGE-RELATED MACULAR DEGENERATION - CLINICAL-FEATURES IN A LARGE FAMILY AND LINKAGE TO CHROMOSOME 1Q

Objectives: To identify the chromosomal location of a disease-causing gene and to describe the clinical characteristics of a large family wi th age-related macular degeneration (ARMD). Methods: An ARMD pedigree was identified, and the disease state of family members was documented by stereoscopic fundus photography and was classified using a modifie d version of the Wisconsin Age-Related Maculopathy Grading System. A g enome-wide screen at approximately 6-centimorgan spacing using a DNA-p ooling strategy combined with shared-segment analysis was used to iden tify likely chromosomal regions. The entire family was then screened a t each likely locus, and 1 positive locus was refined by screening wit h markers at an average density of 0.5 centimorgan and subjected to pa rametric linkage analysis. Results: In the 10 affected family members, ARMD was manifest by the presence of large, soft, confluent drusen ac companied by varying degrees of retinal pigment epithelial degeneratio n and/or geographic atrophy. Age-related macular degeneration segregat ed as an autosomal-dominant trait, with the disease locus mapping to c hromosome 1q25-q31 between markers D1S466 and D1S413, with a multipoin t lod score of 3.00. Conclusion: Age-related macular degeneration loca lized to chromosome 1q25-q31 (gene symbol, ARMD1) as a dominant trait in a large family with a predominantly dry phenotype. Clinical Relevan ce: Identification of ARMD genes will facilitate early diagnosis and a id in understanding the molecular pathophysiological mechanisms of ARM D. This knowledge will contribute to the development of preventive and improved treatment strategies.