Genomewide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3-q21.1.
OBJECTIVE
Keratoconus is a corneal dystrophy with an incidence of 1 in 2000 and a leading cause for cornea transplantation in Western developed countries. Both clinical observations and segregation analyses suggest a major role for genes in its pathogenesis. It is genetically heterogeneous, most commonly sporadic, but inherited patterns with recessive or dominant modes have also been reported. We studied a four-generation autosomal-dominant pedigree to identify disease loci for keratoconus.


METHODS
A two-stage genome-wide scan was applied to 27 family members. First linkage analysis was performed with 343 microsatellite markers along the 22 autosomal chromosomes at approximately 10 cM density. This was followed by fine mapping at approximately 2 cM density, in regions suggestive of linkage. Multipoint linkage analysis was performed using GeneHunter2.


RESULTS
Evidence of suggestive linkage from the initial scan was observed at the 82 to 112 cM region of chromosome 5q14.1-q21.3 with a maximum lod score (LOD) of 3.48 (penetrance = 0.5). Fine mapping by testing an additional 11 microsatellite markers at 1 to 3 cM intervals revealed a narrower and higher peak (99-119 cM) with LOD 3.53. By analysis of the recombination of haplotypes, the putative locus of keratoconus was further narrowed to a 6 cM region (8.2 Mbp physical distance) between markers D5S2499 and D5S495.


CONCLUSIONS
These results indicate a promising new locus for keratoconus in this pedigree. Because of the heterogeneous nature of keratoconus, this locus may be specific to familial autosomal-dominant keratoconus. Nevertheless, the identification of this locus may provide new insights into the pathogenesis of keratoconus.
Tang
Yongming G
YG
Medical Genetics Institute, Cedars-Sinai Medical Center, 665W 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
Rabinowitz
Yaron S
YS
Taylor
Kent D
KD
Li
Xiaohui
X
Hu
Mingshu
M
Picornell
Yoana
Y
Yang
Huiying
H
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007640:Keratoconus / Q000453:epidemiology / Q000235:genetics*; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010375:Pedigree; D019683:Penetrance; D044465:White People
D005819:Genetic Markers