Linkage analysis with chromosome 15qll-13 markers shows genomic imprinting in familial Angelman syndrome

Abstract

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) have become the classical examples of genomic imprinting in man, as completely different phenotypes are generated by the absence of maternal (AS) or paternal (PWS) contributions to the qll-13 region of chromosome 15 as a result of deletion or uniparental disomy. Apparently, most patients are sporadic cases. The genetic mechanism underlying familial AS has remained enigmatic for a long time. Recently, evidence has been emerging suggesting autosomal dominant inheritance of a detectable or undetectable defect in a gene or genes at 15ql 1-13, subject to genomic imprinting. The present report describes an unusually large pedigree with segregation of AS through maternal inheritance and apparent asymptomatic transmission through several male ancestors. Deletion and paternal disomy at 15ql1-13 were excluded. However, the genetic defect is still located in this region, as we obtained a maximum lod score of 5 40 for linkage to the GABA receptor locus GABRB3 and the anonymous DNA marker DISSlO, which have been mapped within or adjacent to the AS critical region at 15qll-13. The size of the pedigree allowed calculation of an odds ratio in favour of genomic imprinting of 9 25 x 105. This family illustrates the necessity of extensive pedigree analysis when considering recurrence risks for relatives of AS patients, those without detectable deletion or disomy in particular.