1. ¹Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany
2. ²Institut für Humangenetik, Charité, Humboldt Universität Berlin, Berlin, Germany

Correspondence: Dr K Buiting, Institut für Humangenetik, Universitätsklinikum Essen, 45122 Essen, Germany. Tel: +49 201 723 4555; Fax: +49 201 723 5900; E-mail: karin.buiting@uni-essen.de

Received 22 July 2005; Revised 16 January 2006; Accepted 8 February 2006; Published online 5 April 2006.

Abstract

In the majority of patients with a chromosome 15 imprinting defect (ID) causing Prader–Willi syndrome (PWS) or Angelman syndrome (AS), the defect is a primary epimutation that occurred spontaneously in the absence of a DNA mutation. We have investigated whether common DNA sequence variants in the bipartite imprinting centre (IC) are associated with an increased susceptibility to imprinting defects. We have determined the haplotype structure of the IC and found that the two IC elements called 'PWS-SRO' and 'AS-SRO' lie on separate haplotype blocks. To identify susceptible IC sequence variants, we have used the transmission disequilibrium test. While we did not observe preferential transmission of a paternal allele or haplotype in 41 PWS-ID trios, we found a trend for preferential maternal transmission of one AS-SRO haplotype (H-AS3) in 48 AS-ID trios (P=0.058) and could identify two sequence variants in H-AS3 that are responsible for this effect. We also obtained tentative evidence that homozygosity for the 677C>T variant of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene on chromosome 1 might increase the risk of a maternal imprinting defect: the frequency of the TT genotype was significantly higher in the mothers of the AS patients with an imprinting defect than in the patients' fathers or the general population (P=0.028). Our findings suggest that women with the IC haplotype H-AS3 or homozygosity for the MTHFR 677C>T variant may have an increased risk of conceiving a child with an imprinting defect, although the absolute risk is low.