Homozygosity mapping and linkage analysis demonstrate that autosomal recessive congenital hereditary endothelial dystrophy (CHED) and autosomal dominant CHED are genetically distinct

Abstract

Background: Congenital hereditary endothelial dystrophy (CHED) is a corneal dystrophy characterised by diffuse bilateral corneal clouding resulting in impaired vision. It is inherited in either an autosomal dominant (AD) or autosomal recessive (AR) manner. The AD form of CHED has been mapped to the pericentromeric region of chromosome 20. Another endothelial dystrophy, posterior polymorphous dystrophy (PPM), has been linked to a larger but overlapping region on chromosome 20. A large, Irish, consanguineous family with AR CHED was investigated to determine if there was linkage to this region.

Methods: The technique of linkage analysis with polymorphic microsatellite markers amplified by polymerase chain reaction (PCR) was used. In addition, a DNA pooling approach to homozygosity mapping was employed to demonstrate the efficiency of this method.

Results: Conventional genetic analysis in addition to a pooled DNA strategy excludes linkage of AR CHED to the AD CHED and larger PPMD loci.

Conclusion: This demonstrates that AR CHED is genetically distinct from AD CHED and PPMD.

Figure 1

Pedigree drawing of family affected with autosomal recessive congenital hereditary endothelial dystrophy. Filled symbols indicate clinically affected individuals, open symbols indicate unaffected individuals or those whose disease status was not established. DNA was available from the individuals indicated by an asterisk; all these individuals were examined by an ophthalmologist.

Figure 2

Silver stained polyacrylamide gels of the PCR products of pooled DNA at the five polymorphic microsatellite markers closely linked to the dominant congenital hereditary endothelial dystrophy locus. In all cases lane 1 is pool of DNA from unaffected individuals, lane 2 is pool of DNA from affected individuals, lane 3 is negative PCR control, and lane 4 is DNA from CEPH individuals 1331-01 and 1331-02 combined. There is no reduction in the number of alleles in pooled DNA from affected individuals compared with pool of unaffected DNA, indicating no increased homozygosity in this region.

Figure 3

Map of the pericentromeric region of chromosome 20 indicating the position of the microsatellite markers analysed and the genetic distances from which linkage has been excluded.