Statistics from Altmetric.com
Editor,—Congenital hereditary endothelial dystrophy (CHED) and posterior polymorphous corneal dystrophy (PPCD) are phenotypically distinct diseases of the corneal endothelium. Linkage analysis has mapped a locus for autosomal dominant PPCD to chromosome 20p11.1 Subsequently, other researchers placed a locus for autosomal dominant CHED (designated CHED1 by the human genome mapping workshop) in an overlapping genetic interval,2 suggesting that these two disorders may be allelic variants of the same defective gene.
However, CHED is more commonly inherited as an autosomal recessive (AR) disease,3 and linkage analysis in a large consanguineous recessive Saudi Arabian pedigree excluded CHED1 as the causative locus.4 Genetic heterogeneity in this condition was further confirmed by linkage analysis in a large consanguineous Irish pedigree5 in which a second CHED genetic locus (CHED2) was subsequently localised more distally at 20p13.6
We now present a Pakistani pedigree with AR CHED in whom genetic analysis also confirms linkage to this second region, suggesting that AR CHED is clinically and genetically homogeneous.
Two generations of a large inbred family were examined, in whom the segregation pattern was consistent with an autosomal recessive mode of inheritance (Fig 1). The three affected daughters all gave a typical history of severe non-progressive corneal clouding present from birth, consistent with recessively inherited CHED. Best corrected visual acuity was hand movements in all affected eyes, and examination revealed an avascularly opacified “ground glass” corneal appearance (Fig 2), and the presence of nystagmus.7 The eldest daughter had a unilateral penetrating keratoplasty performed at age 8 years, in the United States. Histological examination on the host button confirmed the diagnosis of CHED.8 The grafted eye had a large postoperative myopic and astigmatic error, but with refractive correction, the surgery had conferred an unquantifiable but useful improvement in visual function. The unaffected members were all asymptomatic with normal vision and a normal anterior segment examination.
This is only the second AR CHED family reported in the literature for which genetic analysis has been carried out. This analysis locates the abnormal gene to the CHED2 locus at chromosome 20p13 (Fig 1) and excludes the CHED1 locus at chromosome 20p11.
Genetic analysis was performed following DNA extraction by standard techniques. Fluorescently tagged polymorphic microsatellite markers were spaced across the CHED1 and the CHED2 loci. Amplified polymerase chain reaction products were detected using an “ABI 377” automated sequencer with GeneScan software.
Five genetic markers spanning the CHED2 locus were analysed (D20S906—3.6 cM—D20S889—2.8 cM—D20S437—1.1 cM—D20S835—2.1 cM—D20S916, with genetic distance as given on the Marshfield integrated genetic map).9 Examination of the haplotypes shown in Figure 1 reveals an area of identity by descent common to all three affected sisters, while the two unaffected sisters are heterozygous for this region. Multipoint linkage analysis with thelinkmap program from the linkage package gave a lod score of 2.64. The previous probability established by previous linkage to these markers of another AR CHED family makes this result statistically significant. In addition three markers spanning the CHED1 locus, approximately 21 cM centromeric from the CHED2 locus, were analysed. Haplotype analysis in this region clearly excludes the CHED1 region from involvement in the disorder in this family.
This is a significant result, particularly since the affected family is from a different racial group. Linkage analysis and clinical examination suggest genetic and clinical homogeneity for this disorder, but the disparate racial origins of the two CHED2 linked families make it likely that they have different mutations. This in turn should aid the identification of the mutant gene, which lies in a gene rich region of the genome.10 This will help affected individuals by allowing diagnosis by genetic testing and consequently permitting accurate genetic counselling. Also, it may provide valuable insights into the cellular biology of the corneal endothelium, which may improve our understanding of this cell layer and its dysfunction in old age and graft failure, both conditions for which there is currently little effective treatment.
The authors gratefully acknowledge the Wellcome Trust, who funded this research (award reference 061682/dcp).
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.