No evidence for additional imprinting defects in Silver-Russell syndrome patients with maternal uniparental disomy 7 or 11p15 epimutation

Silver-Russell syndrome (SRS) is mainly characterised by intrauterine and postnatal growth retardation (IUGR and PNGR), asymmetry, clinodactyly V and craniofacial abnormalities. More than 35% of patients carry a hypomethylation of the telomeric imprinting centre region 1 (ICR1) in 11p15; single patients show a maternal duplication of 11p15. An additional 7-10% of patients with SRS have maternal uniparental disomy of chromosome 7 (mUPD7). Another disorder caused by epigenetic defects is transient neonatal diabetes mellitus (TNDM) which is associated with loss of methylation (LOM) in 6q24. After detecting methylation loss at multiple imprinted loci in patients with TNDM, Mackay et al. recently proposed the existence of a maternal hypomethylation syndrome presenting as TNDM. They therefore concluded that patients with other disorders associated with LOM at one (maternally) methylated locus might also carry LOM at multiple loci. Similar observations have also been reported in Beckwith-Wiedemann syndrome (BWS): nearly 25% of patients displayed abnormal methylation patterns of ICRs additional to those in 11p15. To show whether general hypomethylation is a common phenomenon in imprinting disorders we carried out methylation analyses for the imprinted regions 14q32, 6q24 and the centromeric imprinting region ICR2 on 11p15 for 10 patients with SRS carrying mUPD7 and 22 patients with LOM at the telomeric imprinting region ICR1. We showed that further epigenetic defects did not occur in the groups of SRS with LOM of ICR1 or mUPD7, and that these subentities do not belong to the diseases with a general hypomethylation defect, such as TNDM and BWS.