American Journal zyx of Medical Genetics 467-11 (1993) Cytogenetic and Molecular Analysis in Angelman Syndrome J.L. Zackowski, R.D. Nicholls, B.A. Gray, A. Bent-Williams, W. Gottlieb, P.J. Harris, M.F. Waters, D. J. Driscoll, R.T. zyxwvu Zori, and C.A. Williams zyxwvu R.C. Philips Research and Education Unit, Division zyxwvu of Genetics, Department of Pediatrics (J.L.Z.,R.D.N., B.A.G., A.B.W., P.J.H., M.F.W., D.J.D., R.T.Z., CA.W.1, and Department of Neuroscience (R.D.N., W.G.), University of Florida Health Science Center, Gainesuille, Florida We report on cytogenetic and molecular an- alyses of 29 Angelman syndrome(AS)individ- uals ascertained in 1990 through the first Na- tional Angelman Syndrome Conference.High resolution GTG- and GBG-banded chromo- somes were studied. Standard molecular analysis with six 15qllq13 DNA sequences was used to analyze copy number and paren- tal origin of 15qllq13. Concordance between molecular and cytogenetic data was excellent. The combined data showed that 23 of the 27 probands (85%) on whom we had definitive results have deletions of the chromosome 15qllq13 region. Two classes of deletion were detected molecularly: most patients were de- leted for the 5 more proximal probes, but in 2 cases the deletion extended distally to include in sixth probe. In the 13 cases where the par- ental origin of the deleted chromosome 15 could be established, it was maternal. There were no cases of uniparental disomy. Cyto- logical observations of the relative sizes of the heterochromatic regions of the short arm of chromosome 15 suggested that chromosomes with large heterochromatic blocks may be more prone to de zyxwvuts novo deletion. zyxwvu 0 1993 zyxwvutsrqpo Wiley-Liss, Inc. KEY WORDS: chromosome 15, genomic im- printing, parental origin INTRODUCTION The first cytogenetic observations of an interstitial deletion of chromosome 15qllq13 in Angelman syn- drome (AS) were made in 1987 [Kaplan et al., 1987; Magenis et al., 19871. Numerous reports of chromosome Received for publication March 20, 1992; revision received May 11, 1992. Address reprint requests to C.A. Williams, M.D., Division of Genetics, Department of Pediatrics, University of Florida Health Science Center, Gainesville, FL 32610-0296. 15 deletions in AS have followed [Donlon, 1988; Will- iams et al., 1989a; 1989b;Cooke et al., 1989;Pembrey et al., 1989; Fryns et al., 1989; Imaizumi et al., 1990; Ha- mabe et al., 19911. A similar or identical deletion has been seen in the phenotypically distinct Prader-Willi syndrome (PWS) [Ledbetter et al., 1981, 19821. Knoll et al. [19891 summarized studies on the paren- tal origin of the deleted chromosome 15 in 9 AS patients that were informative either molecularly or cyto- genetically, and demonstrated an exclusive maternal origin. This has been upheld by findings of a maternal origin of the deleted chromosome 15 in subsequent studies of AS [Magenis et al., 1990; Knoll et al., 1990; Williams et al., 19901. In view of the exclusive paternal origin of the deleted chromosome 15qllq13 in PWS [Butler and Palmer, 1983;Butler et al., 1986;Nicholls et al., 1989a; Zori et al., 1990;Robinson et al., 19911, a role for parental genomic imprinting in the cause of AS and PWS was proposed [Knoll et al., 1989; Williams et al., 1990; Hall, 1990;Magenis et al., 19901. This hypothesis was supported to a great extent by the discovery of maternal uniparental disomy for chromosome 15q llq13 in a proportion of PWS cases [Nicholls et al., 198913; Robinson et al., 1991; Mascari et al., 19921. Pa- ternal uniparental disomy has been observed in AS [Malcolm et al., 1991;Nicholls et al., 19921, but appears to be less frequent than in PWS [Knoll et al., 1991; Robinson et al., 1991; Mascari et al., 19921. Thus, in the absence of a paternal copy of 15qllq13,whether caused by interstitial deletion of the paternal chromosome 15 or by maternal uniparental disomy, PWS results; the ab- sence of a maternal contribution at this chromosome region causes the development of AS. Although a number of cytogenetic andor molecular studies in AS have been reported, to date it has been somewhat difficult to establish the parameters defining the molecular nature of the syndrome, because of biases of ascertainment and subjectivities of clinical and cyto- genetic diagnoses. We report here the results of cyto- genetic and molecular studies performed on a population of 29 AS probands and parents of 22 of those probands, who were identified through the Angelman Research Group Repository in the Division of Genetics at the University of Florida Health Science Center. In our z 0 1993 Wiley-Liss, Inc.