Angelman Syndrome: Mosaicism or multi-locus imprinting defect?

Genomic imprinting is the epigenetic marking of a specific gene, resulting in mono-alleleic expression in a parent-of-origin dependent manner. Eight classical imprinting disorders (IDs) have been identified which result from loss of methylation at specific imprinted loci. One disorder, Angelman syndrome (AS), results from the lack of expression of the maternally expressed 15q11-q13 genes. This can be through deletion, paternal uniparental disomy, mutations in UBE3A or an imprinting defect. Interestingly, nearly half of the imprinting defect cases present with a mosaic defect, however, the molecular mechanisms causing this are unclear. Recently, individuals who have abnormal methylation patterns across numerous imprinted regions, named multi-locus imprinting defects (MLIDs), have been identified. Researchers at the University of Cambridge have been developing a multiplex assay which focuses on Beckwith-Wiedemann syndrome (BWS) and other imprinted loci which have been shown to harbour methylation changes in MLID patients. However, this assay and methodology has not been validated for diagnostic purposes and does not include any regions linked to AS. The aim of this project was to setup and validate an assay which would allow mosaic AS samples to be examined further and to investigate whether these patients actually show MLIDs. The validation experiments carried out to date have shown that this next-generation sequencing based method has produced data which will enable quantification of a number of CpG dinucleotides within each region interrogated. These results may therefore help explain an atypical AS presentation which could provide a diagnosis to a patient that may affect their clinical management.