Erschienen:
Springer Science and Business Media LLC, 2020
Erschienen in:
European Journal of Human Genetics, 28 (2020) 6, Seite 835-839
Sprache:
Englisch
DOI:
10.1038/s41431-020-0595-y
ISSN:
1018-4813;
1476-5438
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Angelman syndrome (AS) is a rare neurogenetic imprinting disorder caused by the loss of function of <jats:italic>UBE3A</jats:italic>. In ~3–5% of AS patients, the disease is due to an imprinting defect (ID). These patients lack DNA methylation of the maternal <jats:italic>SNRPN</jats:italic> promotor so that a large <jats:italic>SNRPN</jats:italic> sense/<jats:italic>UBE3A</jats:italic> antisense transcript (<jats:italic>SNHG14</jats:italic>) is expressed, which silences <jats:italic>UBE3A</jats:italic>. In very rare cases, the ID is caused by a deletion of the AS imprinting centre (AS-IC). To search for sequence alterations, we sequenced this region in 168 patients without an AS-IC deletion, but did not detect any sequence alteration. However, the AS-IC harbours six common variants (five single nucleotide variants and one TATG insertion/deletion variant), which constitute five common haplotypes. To determine if any of these haplotypes is associated with an increased risk for an ID, we investigated 119 informative AS-ID trios with the transmission disequilibrium test, which is a family-based association test that measures the over-transmission of an allele or haplotype from heterozygous parents to affected offspring. By this we observed maternal over-transmission of haplotype H-AS3 (<jats:italic>p</jats:italic> = 0.0073). Interestingly, H-AS3 is the only haplotype that includes the TATG deletion allele. We conclude that this haplotype and possibly the TATG deletion, which removes a SOX2 binding site, increases the risk for a maternal ID and AS. Our data strengthen the notion that the AS-IC is important for establishing and/or maintaining DNA methylation at the <jats:italic>SNRPN</jats:italic> promotor and show that common genetic variation can affect genomic imprinting.</jats:p>