Paternal UPD15: Further Genetic and Clinical Studies in Four Angelman Syndrome Patients Cintia Fridman, 1 * Monica C. Varela, 1 Fernando Kok, 2 Aron Diament, 2 and Ce ´ lia P. Koiffmann 1 1 Department of Biology, Institute of Bioscience, University of Sa ˜ o Paulo, Sa ˜ o Paulo, Brazil 2 Child Neurology Service, Department of Neurology, Hospital das Clı ´nicas, University of Sa ˜ o Paulo, School of Medicine, Sa ˜ o Paulo, Brazil Among 25 patients diagnosed with Angel- man syndrome, we detected 21 with deletion and 4 with paternal uniparental disomy (UPD), 2 isodisomies originating by postzy- gotic error, and 1 MII nondisjunction event. The diagnosis was obtained by molecular techniques, including methylation pattern analysis of exon 1 of SNRPN and microsat- ellite analysis of loci within and outside the 15q11-q13 region. Most manifestations pres- ent in deletion patients are those previously reported. Comparing the clinical data from our and published UPD patients with those with deletions we observed the following: the age of diagnosis is higher in UPD group (average 7 3 /12 years), microcephaly is more frequent among deletion patients, UPD chil- dren start walking earlier (average age 2 9 /12 years), whereas in deletion patients the av- erage is 4 1 /2 years, epilepsy started later in UPD patients (average 5 10 /12 years) than in deletion patients (average 1 11 / 12 years), weight above the 75th centile is reported mainly in UPD patients, complete absence of speech is more common in the deleted (88.9%) than in the UPD patients because half of the children are able to say few words. Thus, besides the abnormalities al- ready described, the UPD patients have somewhat better verbal development, a weight above the 75th centile, and OFC in the upper normal range. Am. J. Med. Genet. 92:322–327, 2000. © 2000 Wiley-Liss, Inc. KEY WORDS: Angelman syndrome; 15q de- letion; uniparental disomy; genomic imprinting; meiosis II nondisjunction INTRODUCTION Angelman syndrome (AS) [Angelman, 1965] com- prises hypotonia (90%), severe mental retardation (100%), absent speech (98%), seizures (80%), ataxia (100%), outbursts of laughter, micro and/or brachy- cephaly (90%), macrostomia (75%), and prognathism (95%). The gait is described as wide-based with arms held flexed and upheld at the elbows [Clayton-Smith and Pembrey, 1992; Fryburg et al., 1991; Robb et al., 1989]. The Prader-Willi (PWS) (hypotonia, obesity, and hy- perphagia) and Angelman syndromes are clear ex- amples of genomic imprinting in humans because the clinical manifestation of these syndromes depends on the sex of the parent-of-origin of mutations within the 15q11-q13 region. The genetic basis of AS is complex, and at present, it is unknown whether the syndrome is caused by the loss of function of a single gene or wheth- er different genes are involved [Bu ¨ rger et al., 1997]. About two thirds of the AS cases are due to maternal deletion within 15q11-q13 [Magenis et al., 1987; Knoll et al., 1989]; paternal uniparental disomy of chromo- some 15 (UPD15) is detected in 2–3% [Nicholls, 1993]; approximately 2% of individuals show imprinting con- trol center mutations identified by abnormal methyl- ation pattern [Buiting et al., 1995, 1998; Glenn et al., 1997; Saitoh et al., 1996; Sutcliffe et al., 1994]; about 8% show mutations in the UBE3A gene [Kishino et al., 1997; Malzac et al., 1998; Matsuura et al., 1997], and there is a class of AS patients with undetected genetic mechanism. Recurrence risk in deletion and UPD cases is less than 1% and for familial imprinting mutation and UBE3A mutation may be 50% [Burger et al., 1997; Saitoh et al., 1997]. In general, AS is not suspected during the first year of life, but it is better recognized around 3–4 years of age. Some characteristics, such as seizures, outbursts of laughter, macrostomia, prognathism, and wide- based gait, become more evident after age 2 years; asymmetrical face and scoliosis can occur only at pu- berty [Buntinx et al., 1995]. An electroencephalogram (EEG) study can be useful for diagnosis if some of the AS characteristics are present; nevertheless, some of those manifestations are age-dependent and can disap- pear in older children [Clayton-Smith, 1992]. Grant Sponsor: Department of Energy; Grant Numbers: DOE- FG03-92 ER601402; DOE-FC03-96 ER62294. *Correspondence to: C. Fridman, Departamento de Biologia, Instituto de Biocie ˇncias, USP, Caixa Postal 11.461, CEP: 05422- 970, Sa ˜ o Paulo, SP, Brazil. E-mail: cfridman@ib.usp.br Received 20 October 1999; Accepted 22 February 2000 American Journal of Medical Genetics 92:322–327 (2000) © 2000 Wiley-Liss, Inc.