FAMILIAL CRYPTIC TRANSLOCATION RESULTING IN ANGELMAN SYNDROME - IMPLICATIONS FOR IMPRINTING OR LOCATION OF THE ANGELMAN GENE

Angelman syndrome (AS) is associated with a loss of maternal genetic i nformation, which typically occurs as a result of a deletion at 15q11- q13 or paternal uniparental disomy of chromosome 15. We report a patie nt with AS as a result of an unbalanced cryptic translocation whose br eakpoint, at 15q11.2, falls within this region. The proband was diagno sed clinically as having Angelman syndrome, but without a detectable c ytogenetic deletion, by using high-resolution G-banding. FISH detected a deletion of D15S11 (IR4-3R), with an intact GABRB3 locus. Subsequen t studies of the proband's mother and sister detected a cryptic recipr ocal translocation between chromosomes 14 and 15 with the breakpoint b eing between SNRPN and D15S10 (3-21). The proband was found to have in herited an unbalanced form, being monosomic from 15pter through SNRPN and trisomic for 14pter to 14q11.2. DNA methylation studies showed tha t the proband had a paternal-only DNA methylation pattern at SNRPN, D1 5S63 (PW71), and ZNF127. The mother and unaffected sister, both having the balanced translocation, demonstrated normal DNA methylation patte rns at all three loci. These data suggest that the gene for AS most li kely lies proximal to D15S10, in contrast to the previously published position, although a less likely possibility is that the maternally in herited imprinting center acts in trans in the unaffected balanced tra nslocation carrier sister.