Partial paternal uniparental disomy (UPD) of chromosome 1 in apatient with Stargardt disease

[摘要] Purpose: Stargardt disease (STGD) is the most common juvenilemacular dystrophy, characterized by central visual impairment. Allrecessively inherited cases are thought to be due to mutations in theABCA4 gene, mapped to 1p21-p13.Methods: To describe a form of non-mendelian inheritance in apatient with STGD identified through the course of a conventionalmutational screening performed on 77 STGD families. DNA from the patientand relatives was analyzed for variants in all 50 exons of the ABCA4gene by screening on the ABCR400 microarray; results were confirmed bydirect sequencing. Haplotype analyses, standard and high-resolution (HR)karyotypes, and multiplex ligation-dependent probe amplification (MLPA)were also performed.Results: A patient with STGD caused by the homozygous p.Arg1129Leumutation in the ABCA4 gene was found to be the daughter of anoncarrier mother and a father who was heterozygous for this change.Haplotype analysis suggested that no maternal ABCA4 allele wastransmitted to the patient. Microsatellite markers spanning the entirechromosome 1 identified a homozygous region of at least 4.4 Mb,involving the ABCA4 gene. The cytogenetic study revealed normalfemale karyotype. Further evaluation with MLPA showed the patient had anormal dosage for both copies of the ABCA4 gene, thus suggestingpartial paternal isodisomy but not a maternal microdeletion.Conclusions: We report that recessive STGD can rarely be inheritedfrom only one unaffected carrier parent in a non-mendelian manner. Thisstudy also demonstrates that genomic alterations contribute to only asmall fraction of disease-associated alleles for ABCA4.

[学科分类] 生物化学/生物物理