Common genetic variation in the Angelman syndrome imprinting centre affects the imprinting of chromosome 15.

Angelman syndrome (AS) is a rare neurogenetic imprinting disorder caused by the loss of function of UBE3A. In ~3-5% of AS patients, the disease is due to an imprinting defect (ID). These patients lack DNA methylation of the maternal SNRPN promotor so that a large SNRPN sense/UBE3A antisense transcript (SNHG14) is expressed, which silences UBE3A. 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 (p = 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 SNRPN promotor and show that common genetic variation can affect genomic imprinting.

The origin of imprinting defects in Temple syndrome and comparison with other imprinting disorders.

Temple syndrome (TS14) is a rare imprinting disorder caused by genetic and epigenetic alterations on chromosome 14q32. A subset of these patients shows an imprinting defect (ID) where the paternal allele harbors a maternal epigenotype thus silencing the paternally expressed genes and leading to an increased expression of the maternally expressed genes. We investigated the grandparental origin of the incorrectly imprinted chromosome 14 in a cohort of 13 TS14 ID patients and their families. In seven families grandmaternal and, in six families, grandpaternal inheritance was observed. These results indicate that the ID occurred after imprint erasure in the paternal germ line. While the complete lack of methylation as observed in the majority of TS14 ID patients may be due to an imprint establishment error in the paternal germ line, cases with methylation mosaicism suggest that in general many IDs (TS14, AS, BWS, and SRS) are in fact of somatic origin in the early or late embryo.