MOLECULAR AND CLINICAL-STUDY OF 61 ANGELMAN-SYNDROME PATIENTS

We analyzed 61 Angelman syndrome (AS) patients by cytogenetic and mole cular techniques. On the basis of molecular findings, the patients wer e classified into the following 4 groups: familial cases without delet ion, 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 ca ses, 3 sibs from one family had a molecular deletion involving only 2 loci, D15S10 and GABRB3, which define the critical region for AS pheno types. The parental origin of deletion, both in sporadic and familial cases, was exclusively maternal and consistent with a genomic imprinti ng hypothesis. Among sporadic and familial cases without deletion, no uniparental disomy was found and most of them were shown to inherit ch romosomes 15 from both parents (biparental inheritance). A discrepancy between cytogenetic and molecular deletion was observed in 14 (26%) o f 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, includi ng neurological signs and facial characteristics, were not distinct in each group except for hypopigmentation of skin or hair. Familial case s with submicroscopic deletion were not associated with hypopigmentati on. These findings suggested that a gene for hypopigmentation is locat ed outside the critical region of AS and is not imprinted. (C) 1994 Wi ley-Liss, Inc.