A Case of Stargardt Macular Dystrophy Caused by Uniparental Isodisomy (UPID) and Subsequent Analysis of 830 Stargardt Macular Dystrophy Cases for UPID

Abstract

Abstract: : Purpose: This experiment was designed to identify the disease causing mutation in a patient with Stargardt macular dystrophy. Homozygosity of polymorphisms in and near the ABCA4 gene caused us to hypothesize that the maculopathy in this patient could be caused by uniparental isodisomy (UPID) involving chromosome 1. After discovering UPID in this specific case, 830 additional cases of Stargardt macular dystrophy were screened for this chromosomal abnormality. Methods: The pedigree position of each family member in the pedigree was first confirmed with polymorphic marker analysis. Each sample was then subjected to quantitative polymerase chain reaction (QPCR) analysis to screen for deletions in the ABCA4 gene. Following this, a comprehensive set of genetic markers, distributed across the entirety of chromosome 1, were screened by single strand conformation polymorphism (SSCP) analysis in an attempt to detect UIPD. Finally, a population of 830 Stargardt macular dystrophy DNA samples were subjected to similar genotypic analysis of chromosome 1 to screen for UPID. Results: QPCR analysis of the individual members of the original pedigree demonstrated that each individual harbored two copies of the ABCA4 gene. The proband was homozygous for all chromosome 1 markers. Furthermore, all alleles on chromosome 1 of the proband were compatible with the paternal haplotype and half were incompatible with the maternal haplotype. Subsequent marker analysis of 830 additional cases of Stargardt macular dystrophy did not detect any other samples that were homozygous across chromosome 1. Conclusions: The cause of Stargardt macular dystrophy in this pedigree was found to be paternal uniparental isodisomy. However, analysis of an additional 830 cases of Stargardt macular dystrophy revealed that none were due to UPID. To our knowledge, this is the first reported case of Stargardt macular dystrophy due to UIPD and the findings in this study also suggest a lower frequency for UPID of chromosome 1 among recessive disease populations than has previously been suspected.

Keywords: retinal degenerations: hereditary • genetics • macula/fovea