title: Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation.
abstract: 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.
authors.affiliation: Center for Applied Human Molecular Genetics, The Kennedy Center, Glostrup, Denmark. kag@kennedy.dk
authors.forename: Karen
authors.initials: K
authors.lastname: Grønskov
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Poole
authors.forename: Johanne M D
authors.initials: JM
authors.lastname: Hahnemann
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thomson
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tümer
authors.forename: Karen
authors.initials: K
authors.lastname: Brøndum-Nielsen
authors.forename: Rinki
authors.initials: R
authors.lastname: Murphy
authors.forename: Kirstine
authors.initials: K
authors.lastname: Ravn
authors.forename: Linea
authors.initials: L
authors.lastname: Melchior
authors.forename: Alma
authors.initials: A
authors.lastname: Dedic
authors.forename: Birgitte
authors.initials: B
authors.lastname: Dolmer
authors.forename: I Karen
authors.initials: IK
authors.lastname: Temple
authors.forename: Susanne E
authors.initials: SE
authors.lastname: Boonen
authors.forename: Deborah J G
authors.initials: DJ
authors.lastname: Mackay
mesh_terms: D000328:Adult; D000483:Alleles; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D023061:Gene Order; D015321:Gene Rearrangement / Q000235:genetics*; D006801:Humans; D007223:Infant; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D056730:Silver-Russell Syndrome / Q000235:genetics*
chemical_list: C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II