Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation

Karen Grønskov; Rebecca L Poole; Johanne M D Hahnemann; Jennifer Thomson; Zeynep Tümer; Karen Brøndum-Nielsen; Rinki Murphy; Kirstine Ravn; Linea Melchior; Alma Dedic; Birgitte Dolmer; I Karen Temple; Susanne E Boonen; Deborah J G Mackay

doi:10.1136/jmg.2010.086504

Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation

Karen Grønskov, Rebecca L Poole, Johanne M D Hahnemann, Jennifer Thomson, Zeynep Tümer, Karen Brøndum-Nielsen, Rinki Murphy, Kirstine Ravn, Linea Melchior, Alma Dedic, Birgitte Dolmer, I Karen Temple, Susanne E Boonen, Deborah J G Mackay

Medical Genetics Program

31 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medical Genetics
Volume	48
Issue number	5
Pages (from-to)	308-11
Number of pages	4
ISSN	1468-6244
DOIs	https://doi.org/10.1136/jmg.2010.086504
Publication status	Published - 1 May 2011

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Grønskov, K., Poole, R. L., Hahnemann, J. M. D., Thomson, J., Tümer, Z., Brøndum-Nielsen, K., Murphy, R., Ravn, K., Melchior, L., Dedic, A., Dolmer, B., Temple, I. K., Boonen, S. E., & Mackay, D. J. G. (2011). Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation. Journal of Medical Genetics, 48(5), 308-11. https://doi.org/10.1136/jmg.2010.086504

Grønskov, K, Poole, RL, Hahnemann, JMD, Thomson, J, Tümer, Z, Brøndum-Nielsen, K, Murphy, R, Ravn, K, Melchior, L, Dedic, A, Dolmer, B, Temple, IK, Boonen, SE & Mackay, DJG 2011, 'Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation', Journal of Medical Genetics, vol. 48, no. 5, pp. 308-11. https://doi.org/10.1136/jmg.2010.086504

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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.",

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AU - Grønskov, Karen

AU - Poole, Rebecca L

AU - Hahnemann, Johanne M D

AU - Thomson, Jennifer

AU - Tümer, Zeynep

AU - Brøndum-Nielsen, Karen

AU - Murphy, Rinki

AU - Ravn, Kirstine

AU - Melchior, Linea

AU - Dedic, Alma

AU - Dolmer, Birgitte

AU - Temple, I Karen

AU - Boonen, Susanne E

AU - Mackay, Deborah J G

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N2 - 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.

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.

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DO - 10.1136/jmg.2010.086504

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ER -

Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation

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