title: Angelman syndrome and severe infections in a patient with de novo 15q11.2-q13.1 deletion and maternally inherited 2q21.3 microdeletion.
abstract: Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, severe speech disorder, facial dysmorphism, secondary microcephaly, ataxia, seizures, and abnormal behaviors such as easily provoked laughter. It is most frequently caused by a de novo maternal deletion of chromosome 15q11-q13 (about 70-90%), but can also be caused by paternal uniparental disomy of chromosome 15q11-q13 (3-7%), an imprinting defect (2-4%) or in mutations in the ubiquitin protein ligase E3A gene UBE3A mostly leading to frame shift mutation. In addition, for patients with overlapping clinical features (Angelman-like syndrome), mutations in methyl-CpG binding protein 2 gene MECP2 and cyclin-dependent kinase-like 5 gene CDKL5 as well as a microdeletion of 2q23.1 including the methyl-CpG binding domain protein 5 gene MBD5 have been described. Here, we describe a patient who carries a de novo 5Mb-deletion of chromosome 15q11.2-q13.1 known to be associated with Angelman syndrome and a further, maternally inherited deletion 2q21.3 (~364kb) of unknown significance. In addition to classic features of Angelman syndrome, she presented with severe infections in the first year of life, a symptom that has not been described in patients with Angelman syndrome. The 15q11.2-q13.1 deletion contains genes critical for Prader-Willi syndrome, the Angelman syndrome causing genes UBE3A and ATP10A/C, and several non-imprinted genes: GABRB3 and GABRA5 (both encoding subunits of GABA A receptor), GOLGA6L2, HERC2 and OCA2 (associated with oculocutaneous albinism II). The deletion 2q21.3 includes exons of the genes RAB3GAP1 (associated with Warburg Micro syndrome) and ZRANB3 (not disease-associated). Despite the normal phenotype of the mother, the relevance of the 2q21.3 microdeletion for the phenotype of the patient cannot be excluded, and further case reports will need to address this point.
authors.affiliation: Department of Pediatric Neurology, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: Gerda
authors.initials: G
authors.lastname: Neubert
authors.forename: Katja
authors.initials: K
authors.lastname: von Au
authors.forename: Katrin
authors.initials: K
authors.lastname: Drossel
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.forename: Renate
authors.initials: R
authors.lastname: Nickel
authors.forename: Angela M
authors.initials: AM
authors.lastname: Kaindl
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D017204:Angelman Syndrome / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D007239:Infections / Q000235:genetics* / Q000473:pathology; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: C527986:GABRA5 protein, human; C546273:GABRB3 protein, human; D026901:Membrane Transport Proteins; D011963:Receptors, GABA-A; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases; C426648:ATP10A protein, human