Molecular and clinical study of 61 Angelman syndrome patients

Abstract

We analyzed 61 Angelman syndrome (AS) patients by cytogenetic and molecular techniques. On the basis of molecular findings, the patients were classified into the following 4 groups: familial cases without deletion, familial cases with submicroscopic deletion, sporadic cases with deletion, and sporadic cases without deletion. Among 53 sporadic cases, 37 (70%) had molecular deletion, which commonly extended from D15S9 to D15S12, although not all deletions were identical. Of 8 familial cases, 3 sibs from one family had a molecular deletion involving only 2 loci, D15S10 and GABRB3, which define the critical region for AS phenotypes. The parental origin of deletion, both in sporadic and familial cases, was exclusively maternal and consistent with a genomic imprinting hypothesis. Among sporadic and familial cases without deletion, no uniparental disomy was found and most of them were shown to inherit chromosomes 15 from both parents (biparental inheritance). A discrepancy between cytogenetic and molecular deletion was observed in 14 (26%) of 53 patients in whom cytogenetic analysis could be performed. Ten (43%) of 23 patients with a normal karyotype showed a molecular deletion, and 4 (13%) of 30 patients with cytogenetic deletion, del(15) (q11q13), showed no molecular deletion. Most clinical manifestations, including neurological signs and facial characteristics, were not distinct in each group except for hypopigmentation of skin or hair. Familial cases with submicroscopic deletion were not associated with hypopigmentation. These findings suggested that a gene for hypopigmentation is located outside the critical region of AS and is not imprinted.

Phenotype–genotype correlation in 20 deletion and 20 non-deletion Angelman syndrome patients

“…In the deletion group, microcephaly is more frequent than in previous reports, 9,39 although an exact comparison is difficult to make due to differences in patient ages and measurement parameters used. In the total number of 39 non-deletion patients, microcephaly is observed in 16 cases (41%).…”

“…[5][6][7][8] Phenotypic comparison between deletion and non-deletion AS patients has been reported in only two studies. 9,10 There were no significant differences except for hypopigmentation, found only in deletion cases. A milder phenotype in paternal UPD cases has been suggested by different authors.…”

“…The frequency of epilepsy previously reported for deletion patients was 100% and 96%. 9,38 In non-deletion patients, epilepsy is less frequent; it was reported in 19/38 cases (50%). [11][12][13][14][15][16][17]40,41,43 Severe mental retardation and a marked lack of expressive speech are obvious and permanent features of AS in late infancy.…”

“…2,18 Apart from the pigmentary abnormalities associated with deletion cases, 9 non-deletion patients nevertheless seemed to have a milder phenotype than deletion ones. To confirm this putative genotypephenotype correlation, we compared the clinical manifestations of a group of 20 non-deletion AS patients consisting of UPD, imprinting mutations, and UBE3A mutations to those of an age-matched control group of 20 deletion cases.…”

Behavior and neuropsychiatric manifestations in Angelman syndrome

“…The behavioral aspects of a large number of patients with Angelman syndrome have been reported (eg, Robb et al 1989;Fryburg et al 1991;Zori et al 1992;Clayton-Smith 1993;Jolleff and Ryan 1993;Penner et al 1993;Bottani et al 1994;Saitoh et al 1994;Buntinx et al 1995;Bürger et al 1996;Laan et al 1996;Smith et al 1996;Hou et al 1997;Buckley et al 1998;Moncla et al 1999;Dan and Cheron 2003). This has led to preliminary delineation of a constellation of features including prominent laughter, hyperactivity, peculiar communication pattern, mouthing of objects and motor stereotypies.…”