RT Journal Article
SR Electronic
T1 Deletions and rearrangements of the <em>H19</em>/<em>IGF2</em> enhancer region in patients with Silver–Russell syndrome and growth retardation
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 308
OP 311
DO 10.1136/jmg.2010.086504
VO 48
IS 5
A1 Karen Grønskov
A1 Rebecca L Poole
A1 Johanne M D Hahnemann
A1 Jennifer Thomson
A1 Zeynep Tümer
A1 Karen Brøndum-Nielsen
A1 Rinki Murphy
A1 Kirstine Ravn
A1 Linea Melchior
A1 Alma Dedic
A1 Birgitte Dolmer
A1 I Karen Temple
A1 Susanne E Boonen
A1 Deborah J G Mackay
YR 2011
UL http://jmg.bmj.com/content/48/5/308.abstract
AB Silver–Russell syndrome (SRS) is characterised by prenatal and postnatal growth retardation, dysmorphic facial features, and body asymmetry. In 35–60% of SRS cases the paternally methylated imprinting control region (ICR) upstream of the H19 gene (H19-ICR) is hypomethylated, leading to downregulation of IGF2 and bi-allelic expression of H19. H19 and IGF2 are reciprocally imprinted genes on chromosome 11p15. The expression is regulated by the imprinted methylation of the ICR, which modulates the transcription of H19 and IGF2 facilitated by enhancers downstream of H19. A promoter element of IGF2, IGF2P0, is differentially methylated equivalently to the H19-ICR, though in a small number of SRS cases this association is disrupted—that is, hypomethylation affects either H19-ICR or IGF2P0.Three pedigrees associated with hypomethylation of IGF2P0 in the probands are presented here, two with paternally derived deletions, and one with a balanced translocation of inferred paternal origin. They all have a breakpoint within the H19/IGF2 enhancer region. One proband has severe growth retardation, the others have SRS.This is the first report of paternally derived structural chromosomal mutations in 11p15 causing SRS. These cases define a novel aetiology of the growth retardation in SRS, namely, dissociation of IGF2 from its enhancers.