Linkage of late-onset Fuchs corneal dystrophy to a novel locus at 13pTel-13q12.13.
OBJECTIVE
To identify the gene locus underlying the inheritance of late-onset Fuchs corneal dystrophy (FCD) in a large white kindred.


METHODS
Genotypes of small tandem repeat polymorphisms were obtained from 17 affected and 3 unaffected family members, followed by genetic linkage analysis.


RESULTS
In this family, classic late-onset FCD appeared to be inherited as a single, dominant Mendelian trait. In two exceptional sibships, however, children aged 10 and 13 years had FCD. In each sibship, both parents were found to be affected, opening the possibility that this unusually early age of onset was the result of homozygosity for an FCD mutation. Genotype results, however, were not consistent with consanguinity of the parents, who appear to have independent cases of FCD. A whole-genome linkage scan mapped FCD to a single locus at 13pTel-13q12.13, with significant two-point LOD scores of 3.91 at D13S1236 and 3.80 at D13S1304. The 26.4-Mb disease interval contains the chromosome 13 nucleolus organizer (RNR1), the centromere, and 44 annotated protein-encoding genes. So far, exons of 10 of these genes have been screened, but no mutations have been found.


CONCLUSIONS
FCD1 is the first genetic locus to be identified for late-onset FCD, a common disease of the aging cornea. The exceptional early onset of the disease observed in two children is unusual and might be the result of digenic interaction between FCD1 and an independent late-onset FCD mutation.
Sundin
Olof H
OH
Center for Corneal Genetics, Cornea and External Disease Service, The Johns Hopkins University, Baltimore, Maryland, USA.
Jun
Albert S
AS
Broman
Karl W
KW
Liu
Sammy H
SH
Sheehan
Siobhan E
SE
Vito
Elizabeth C L
EC
Stark
Walter J
WJ
Gottsch
John D
JD
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics*; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree