Molecular mechanism of Angelman syndrome in two large families involves animprinting mutation

Patients with Angelman syndrome (AS) and Prader-Willi syndrome with mutatio ns in the imprinting process have biparental inheritance but uniparental DN A methylation and gene expression throughout band 15q11-q13. In several of these patients, microdeletions upstream of the SNRPN gene have been identif ied, defining an imprinting center (IC) that has been hypothesized to contr ol the imprint switch process in the female and male germlines. We have now identified two large families (AS-O and AS-F) segregating an AS imprinting mutation, including one family originally described in the first genetic l inkage of AS to 15q11-q13. This demonstrates that this original linkage is for the 15q11-q13 IC. Affected patients in the AS families have either a 5. 5- or a 15-kb microdeletion, one of which narrowed the shortest region of d eletion overlap to 1.15 kb in all eight cases. This small region defines a component of the IC involved in AS (ie., the paternal-to-maternal switch el ement). The presence of an inherited imprinting mutation in multiple unaffe cted members of these two families, who are at risk for transmitting the mu tation to affected children or children of their daughters, raises importan t genetic counseling issues.