Autosomal Dominant Keratoconus and Developmental Cataract: Linkage to Chromosome 15

Abstract

Abstract: : Purpose: We have identified a 4-generation Irish family with autosomal dominant keratoconus and early developmental cataract. The purpose of this study is to map the disease locus in this family and identify a genetic locus for keratoconus. Methods: Forty-one members of the family were examined on 2 occasions at an interval of 5 years to establish the clinical phenotype and document the onset and progression of the disease. Eighteen members were affected and 21 were unaffected, 2 were too young for a definitive diagnosis. A candidate gene approach to known cataract loci was initially undertaken. Linkage was not identified. A genome-wide search for linkage was then performed on DNA from 29 members of the family using the MD10 linkage mapping panel (ABI) of 400 highly polymorphic microsatellite markers at intervals of approximately 10 cM throughout the genome. Markers were amplified individually using PCR and pooled before sizing on an ABI 3100 genetic analyser using ROX400 standards. Linkage was assessed using the FASTLINK version of LINKAGE. Results: Results: Linkage analysis identified a locus for keratoconus and cataract on chromosome 15 with a 2-point lod score of 5.49. Screening of several potential candidate genes at the locus has failed to reveal any mutations. Conclusions: We present a large family with severe, highly penetrant autosomal dominant keratoconus and developmental cataract with linkage to chromosome 15. It is hoped that this knowledge will help to shed light on the pathogenesis of keratoconus.

Keywords: keratoconus • genetics • cornea: clinical science