DIFFERENT MECHANISMS AND RECURRENCE RISKS OF IMPRINTING DEFECTS IN ANGELMAN-SYNDROME

Angelman syndrome (AS) is a neurogenetic disorder that appears to be c aused by the loss of function of an imprinted gene expressed from mate rnal chromosome 15 only. Approximately 6% of patients have a paternal imprint on the maternal chromosome. In a few cases, this is due to an inherited microdeletion, in the 15q11-q13 imprinting center (IC), that blocks the paternal-->maternal imprint switch in the maternal germ li ne. We have determined the segregation of 15q11-q13 haplotypes in nine families with AS and with an imprinting defect. One family, with two affected siblings, has a microdeletion affecting the IC transcript. In the other eight patients, no mutation was found at this locus. In two families, the patient and a healthy sibling share the same maternal a lleles. In one of these families and in two others, grandparental DNA samples were available, and the chromosomes with the imprinting defect were found to be of grandmaternal origin. These findings suggest that germ-line mosaicism or de novo mutations account for a significant fr action of imprinting defects, among patients who have an as-yet-undete cted mutation in a cis-acting element. Alternatively, these data may i ndicate that some imprinting defects are caused by a failure to mainta in or to reestablish the maternal imprint in the maternal germ line or by a failure to replicate the imprint postzygotically. Depending on t he underlying cause of the imprinting defect, different recurrence ris ks need to be considered.