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Exceptionally mild Angelman syndrome phenotype associated with an incomplete imprinting defect
  1. K Brockmann1,
  2. R Böhm1,*,
  3. J Bürger2,†
  1. 1Department of Paediatrics and Neuropaediatrics, Children's Hospital, Georg-August-University, Göttingen, Germany
  2. 2Institute of Human Genetics, Virchow-Klinikum, Humboldt University, Berlin, Germany
  1. Correspondence to:
 Dr K Brockmann, Department of Paediatrics and Neuropaediatrics, Children's Hospital, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany;
 kbrock{at}med.uni-goettingen.de

https://doi.org/10.1136/jmg.39.9.e51

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    A ngelman syndrome (AS) is a relatively frequent disorder of mental and motor development. Affected subjects show severe mental retardation, delayed motor development, movement or balance disorders with ataxic gait and jerky limb movements, and absence of speech. In addition, distinct behavioural features, such as frequent laughter and hyperactivity, microcephaly, seizures, and EEG abnormalities are typically found.1

    AS is caused by the loss of function of the maternal UBE3A gene. Structural mutations of the UBE3A gene are found in AS patients, suggesting that UBE3A is the major AS gene.2,3 More than two thirds of AS patients have a de novo deletion of approximately 4 Mb of the maternal chromosome region 15q11-q13, which affects several imprinted genes including UBE3A and SNRPN. Only about 1% of AS cases are the result of paternal disomy of chromosome 15. Finally, approximately 5% of AS patients have an imprinting defect (ID). Apparently normal chromosomes of biparental origin carry uniparental DNA methylation because of a maternal chromosome that erroneously carries a paternal methylation pattern.4 In some of these patients the incorrect epigenotype is caused by a deletion in the imprinting centre,5,6 but other mechanisms must exist as well.7

    Several investigations with small numbers of AS patients suggested a genotype-phenotype correlation. Deletions appeared to correlate with a more severe phenotype than the other three mutation types. AS patients with imprinting defects showed microcephaly and hypopigmentation less frequently,8 those with UBE3A mutations were less severe affected than deletion patients,9 and AS patients with uniparental disomy showed better verbal development compared to deletion patients.10 Furthermore, an intermediate phenotype that more resembles Prader-Willi syndrome than AS was shown to be associated with AS imprinting defects.11

    Recently, Lossie et al12 reported a distinct genotype-phenotype correlation resulting from analysis …

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