DELETIONS AND REARRANGEMENTS OF THE H19/IGF2 ENHANCER REGION IN PATIENTS WITH SILVER-RUSSELL SYNDROME AND GROWTH RETARDATION

Karen Grønskov (1) , Rebecca L Poole (2) , Johanne M. D. Hahnemann (1) , Jennifer Thomson (3) , Zeynep Tumer (1) , Karen Brondum-Nielsen (1) , Rinki Murphy (4) , Kirstine Ravn (1) , Linea Melchior (5) , Alma Dedic (5) , Birgitte Dolmer (6) , I Karen Temple (7) , Susanne E Boonen (5) , Deborah J G Mackay (2)

1 Kennedy Center
2 Salisbury District Hospital
3 Yorkshire Regional Clinical Genetics Service
4 University of Auckland [Auckland]
5 Kennedy Center
6 Naestved Hospital
7 University of Southhampton

Silver-Russell syndrome is characterized by pre- 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 down regulation of IGF2 and biallelic 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, i.e. hypomethylation affects either H19-ICR or IGF2P0. Here we present three pedigrees associated with hypomethylation of IGF2P0 in the probands, 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. We propose that these cases define a novel etiology of the growth retardation in SRS, namely, dissociation of IGF2 from its enhancers.

Mots clés: Diagnosis; Molecular genetics

Karen Grønskov, Rebecca L Poole, Johanne M. D. Hahnemann, Jennifer Thomson, Zeynep Tumer, et al.. DELETIONS AND REARRANGEMENTS OF THE H19/IGF2 ENHANCER REGION IN PATIENTS WITH SILVER-RUSSELL SYNDROME AND GROWTH RETARDATION. Journal of Medical Genetics, 2011, 48 (5), pp.308. ⟨10.1136/jmg.2010.086504⟩. ⟨hal-00604048⟩