RESEARCH ARTICLE Angelman Syndrome in Denmark. Birth Incidence, Genetic Findings, and Age at Diagnosis Line Granild Bie Mertz, 1 * Rikke Christensen, 2 Ida Vogel, 2 Jens Michael Hertz, 3 Karen Brøndum Nielsen, 4 Karen Grønskov, 4 and John R. Østergaard 1 1 Department of Pediatrics, Center for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark 2 Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark 3 Department of Clinical Genetics, Odense University Hospital, Odense, Denmark 4 Medical Genetics Laboratory Center–Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark Manuscript Revised: 7 December 2012; Manuscript Accepted: 20 April 2013 Angelman syndrome (AS) is a neurogenetic disorder caused by loss of expression of the maternal imprinted gene UBE3A on chromosome 15q11.2–q13. Clinical features of AS include severe intellectual disability, a happy disposition, ataxia, mandibular prognatism, and epilepsy. Our objectives were to examine the birth incidence of AS in Denmark and to characterize the size of the 15q11.2–q13 deletions with 1,000K array CGH. In addition, we analyzed genotype differences in regard to age at diagnosis and investigated the occurrence of deletions/duplications out- side the 15q11.2–q13 regions. We identified 51 patients with genetically verified AS, which corresponded to a birth incidence of 1:24,580 (95%CI: 1:23,727–1:25,433). Thirty-six patients showed a deletion; 13 had a Class I deletion and 20 had a Class II deletion. There was bimodal distribution of the BP3 break- point. Three patients had larger and atypical deletions, with distal breakpoints telomeric to BP3. Five patients had paternal uniparental disomy (pUPD) of chromosome 15, and four had a verified UBE3A mutation. Additional deletions/duplications outside the 15q11.2–q13 areas were demonstrated in half the participants. Six harbored more than one CNV. Mean age at diagnosis was 21 months (95%CI: 17–23 months) for children with a deletion and 46 months (95%CI: 36–55 months) for children with pUPD or a UBE3A mutation (P < 0.01). The presence of a CNV outside 15q11.2–q13 did not have an impact on age at diagnosis. Ó 2013 Wiley Periodicals, Inc. Key words: Angelman syndrome; 15q11.2–q13; birth incidence; deletion; breakpoints; array CGH; copy number variation INTRODUCTION Angelman syndrome (AS) is a neurogenetic disorder caused by loss of expression of the maternal imprinted gene, UBE3A, which codes for the protein E6AP ubiquitin-protein ligase. UBE3A is a biallelic gene expressed in all tissues except in the brain [Abu-Amero et al., 2006]. Clinical features of AS include severe intellectual disability and developmental delay, lack of speech, a happy disposition, and ataxia. With age many develop mandibular prognatism. Eighty- ninety percent of patients with AS are reported to have epileptic seizures [Williams et al., 2006; Conant et al., 2009]. The birth incidence of AS is estimated at between 1:10,000 and 1:40,000 [Petersen et al., 1995; Buckley et al., 1998; Oiglane-Shlik et al., 2006; Thomson et al., 2006]. However, previous reports included only a limited number of patients, contained individuals without a ge- netically verified diagnosis, or were prone to ascertainment bias. The true birth incidence of AS is therefore uncertain. Four known molecular mechanisms lead to a deficiency in maternal UBE3A expression and consequently to AS [Tan et al., 2011]: (1) Deletion of the AS critical region on the maternal chromosome 15q11.2–q13 (70%), (2) paternal uniparental disomy (pUPD) (2–7%), (3) imprinting defects (3–5%), and (4) mutations in the maternal copy of UBE3A (10%). Among individuals with a 15q11.2–q13 deletion, a minority has a 5.9 Mb (Class I) deletion, whereas the remainder has a smaller 5.0 Mb (Class II) deletion. These deletions differ only in the location of the centromeric breakpoints of the deletion How to Cite this Article: Mertz LGB, Christensen R, Vogel I, Hertz JM, Nielsen KB, Grønskov K, Østergaard JR. 2013. Angelman syndrome in Denmark. Birth incidence, genetic findings, and age at diagnosis. Am J Med Genet Part A 161A:2197–2203.  Correspondence to: Line Granild Bie Mertz, Department of Pediatrics Aarhus, Center for Rare Diseases, University Hospital, Aarhus Brendstrupgaardsvej 100, 8200 Aarhus N, Denmark. E-mail: linebiemertz@dadlnet.dk Article first published online in Wiley Online Library (wileyonlinelibrary.com): 2 August 2013 DOI 10.1002/ajmg.a.36058 Ó 2013 Wiley Periodicals, Inc. 2197