title: Apparent autosomal dominant keratoconus in a large Australian pedigree accounted for by digenic inheritance of two novel loci.
abstract: Keratoconus is a debilitating ocular disease characterised by progressive asymmetrical thinning of the cornea, the clear covering at the front of the eye. The resulting protrusion of the cornea results in severe refractive error, in the most severe cases requiring corneal grafting. It is a complex disease with a genetic component. Despite several reports of linked loci, major gene identification has been elusive. A genome-wide linkage scan in a large Australian pedigree with apparent autosomal dominant keratoconus was conducted using the Affymetrix 10K SNP chip and two regions of linkage identified. Functional candidate genes from within both linkage peaks were assessed for corneal expression and screened for mutations in affected family members. Equal evidence of linkage was detected to both 1p36.23-36.21 and 8q13.1-q21.11 with LOD scores of 1.9. Analysis of both loci concurrently suggests digenic linkage with two-locus LOD score of 3.4. All affected individuals carry identical haplotypes at both loci. Carriers of either linked haplotype without the other do not have keratoconus. No mutations were identified in the following candidate genes expressed in the cornea: ENO1, CTNNBIP1, PLOD1, UBIAD1, SPSB1 or TCEB1. Although the pedigree appears to demonstrate simple autosomal dominant inheritance, the disorder is actually genetically complex. This pedigree may provide a link between inherited forms of keratoconus and sporadic cases.
authors.affiliation: Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, Adelaide, SA, 5042, Australia. kathryn.burdon@flinders.edu.au
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Burdon
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Coster
authors.forename: Jac C
authors.initials: JC
authors.lastname: Charlesworth
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mills
authors.forename: Kate J
authors.initials: KJ
authors.lastname: Laurie
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.forename: Paul
authors.initials: P
authors.lastname: Latimer
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000818:Animals; D001315:Australia / Q000453:epidemiology; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D003315:Cornea / Q000502:physiology; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005799:Genes, Dominant; 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; D051379:Mice; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D044465:White People
chemical_list: D005819:Genetic Markers
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