MOLECULAR MECHANISMS IN ANGELMAN SYNDROME - A SURVEY OF 93 PATIENTS

Angelman syndrome (AS) results from a, lack of maternal contribution f rom chromosome 15q11-13, arising from de novo deletion in most cases o r rarely from uniparental disomy. These families are associated with a low recurrence risk. However, in a minority of families, more than on e child is affected. No deletion has been found in these families,1 2 except one.3 The mode of inheritance in these families is autosomal do minant modified by imprinting. Sporadic cases, with no observable dele tion, therefore pose a counselling dilemma as there could be a recurre nce risk as high as 50%. We present a series of 93 AS patients, showin g the relative contribution of these different genetic mechanisms. Eig hty-one AS patients were sporadic cases while 12 cases came from six f amilies. Sixty cases had deletions in 15q11-13 detected by a set of hi ghly polymorphic (CA)n repeats markers and conventional RFLPs. Ten spo radic cases plus all 12 familial cases had no detectable deletion. In addition, two cases of de novo deletions occurred in a chromosome 15 c arrying a pericentric inversion. In one of these the AS child had a co usin with Prader-Willi syndrome (PWS) arising from a de novo deletion in an inv(15) inherited from his father. One case arose from a materna l balanced t(9;15)(p24;q15) translocation. There were three cases of u niparental disomy. Five patients were monoallelic for all loci across the minimal AS critical region, but the presence of a deletion cannot be confirmed. In familial cases, all affected sibs inherited the same maternal chromosome 15 markers for the region 15q11-13. Two cases were observed with a de novo deletion starting close to the locus D15S11 ( IR4-2R), providing evidence for the development of classical AS with s maller deletions. Cytogenetic analysis proved limited in its ability t o detect deletions, detecting only 42 out of 60 cases. However, cytoge netic analysis is still essential to detect chromosomal abnormalities other than deletions such as inversions and balanced translocations si nce both have an increased risk for deletions. A staged diagnostic str ategy based on the use of highly informative (CA)n repeat markers is p roposed.