NOVEL PATTERNS OF INHERITANCE OF GENETIC-DISEASE ARE ILLUSTRATED BY THE ANGELMAN SYNDROME

Objective: To characterise the molecular abnormalities present in a co hort of patients with the Angelman syndrome. Methods: DNA samples from 10 patients with the Angelman syndrome were investigated with molecul ar probes. Family studies were performed by means of DNA polymorphism analysis and densitometric estimation of allele copy number to determi ne the underlying mutation and its parental origin. Results: Nine prob ands were shown to have molecular (DNA) deletions involving chromosome 15q11-q13. Polymorphism analyses demonstrated that all deletions were maternal in origin. Five of the nine had normal karyotypes, with dele tions only detected after DNA study. One patient had inherited both ch romosomes 15 from her father. This represented an example of paternal uniparental disomy of chromosome 15. Conclusions: Development of the A ngelman syndrome can result from either deletion of the maternally-der ived copy of chromosome 15q11-q13 or the presence of two paternally de rived copies of chromosome 15, that is, uniparental disomy. DNA testin g allows the identification of deletions that are not seen on cytogene tic analysis and can provide additional information regarding the pare ntal origin of the deletion. Uniparental disomy is most readily establ ished by DNA studies.