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Apparent autosomal dominant keratoconus in a large Australian pedigree accounted for by digenic inheritance of two novel loci
journal contribution
posted on 2023-05-17, 08:31 authored by Kathryn BurdonKathryn Burdon, Coster, DJ, Jac CharlesworthJac Charlesworth, Mills, RA, Laurie, KJ, Giunta, C, Alexander HewittAlexander Hewitt, Latimer, P, Craig, JEKeratoconus 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.
History
Publication title
Human GeneticsVolume
124Issue
4Pagination
379-386ISSN
0340-6717Department/School
Menzies Institute for Medical ResearchPublisher
Springer-VerlagPlace of publication
175 Fifth Ave, New York, USA, Ny, 10010Rights statement
Copyright 2008 Springer-VerlagRepository Status
- Restricted