A common locus for late-onset Fuchs corneal dystrophy maps to 18q21.2-q21.32.

PURPOSE: To identify the genetic basis of late-onset Fuchs corneal dystrophy (FCD).

METHODS: Phenotypes and genotypes at 1107 short tandem repeat polymorphism markers were obtained for 43 affected and 33 unaffected individuals in three large families. Two-point genetic linkage analysis was performed with MLINK and multipoint linkage with SimWalk 2.89.

RESULTS: In each family, the most significant cluster of two-point lod scores mapped to chromosome 18, at 18q21.2-q21.3. The highest two-point lod score for each family was at D18S1129, with scores of 3.41, 2.89, and 2.45, with a combined two-point lod score of 7.70. Multipoint analysis yielded a maximum score of 5.94 at D18S1129 for a dominant Mendelian trait exhibiting 85% penetrance and 15% phenocopy rate. Disease interval haplotypes for each family are different.

CONCLUSIONS: FCD2, at 18q21, is the second genetic locus identified for late-onset FCD. Presence of this same locus in all three families may indicate its widespread involvement in late-onset FCD. Allelic differences between disease-associated haplotypes in the families leave open the possibility of independent mutations in the same gene. The incomplete penetrance and high phenocopy rate observed at FCD2 suggest that the origin of FCD in these three families is complex and also depends on other genetic loci or environmental factors.