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Epigenotype-phenotype correlations in Silver-Russell syndrome

Epigenotype-phenotype correlations in Silver-Russell syndrome
Epigenotype-phenotype correlations in Silver-Russell syndrome
Background Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in 5-10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information on the condition. Methods A detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44) was undertaken. Results and conclusions The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation was more likely to be scored as 'classical' SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. The authors report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings, although recurrence risk remains low in the majority of cases. Overall, a wide range of severity was observed, particularly with ICR1 hypomethylation. A low threshold for investigation of patients with features suggestive, but not typical, of SRS is therefore recommended.
0022-2593
760-768
Wakeling, E.L.
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Amero, S.A.
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Alders, M.
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Bliek, J.
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Forsythe, E.
a9635576-31ff-497d-8a07-b6be01409536
Kumar, S.
695e30ec-08ac-4ad7-9f6b-b18dc52bcd0b
Lim, D.H.
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MacDonald, F.
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Mackay, D.J.
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Maher, E.R.
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Moore, G.E.
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Poole, R.L.
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Price, S.M.
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Tangeraas, T.
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Turner, C.L.S.
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Van Haelst, M.M.
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Willoughby, C.
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Temple, I.K.
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Cobben, J.M.
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Wakeling, E.L.
952707d0-4f1f-4240-a5bf-be957d9a28d5
Amero, S.A.
b4164cac-2600-475d-b7ce-8eb6ddadee7c
Alders, M.
346d662f-e908-4f6e-8de8-b37ee8868f2e
Bliek, J.
70763bb6-0210-4e57-ac42-d4a91ea60155
Forsythe, E.
a9635576-31ff-497d-8a07-b6be01409536
Kumar, S.
695e30ec-08ac-4ad7-9f6b-b18dc52bcd0b
Lim, D.H.
81fc08e5-a8ff-4933-b873-a1b4aab3b72e
MacDonald, F.
d4d0c9ce-8628-4502-94f4-ce4a17453357
Mackay, D.J.
588a653e-9785-4a00-be71-4e547850ee4a
Maher, E.R.
cbc3d987-e63b-4f47-b19c-4efd77487c2e
Moore, G.E.
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Poole, R.L.
d8fe00fa-9deb-4a34-a7d8-4b7f57ce82fa
Price, S.M.
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Tangeraas, T.
47e1351a-7634-460f-9b4f-93a3029e33c7
Turner, C.L.S.
2bbfb7e9-db26-4ff5-a1e1-bc19f21c53a8
Van Haelst, M.M.
f4311d24-1bdc-4b5c-b7c4-8f837fd647e0
Willoughby, C.
8991a553-bac5-406f-9390-05c5872d04ab
Temple, I.K.
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Cobben, J.M.
975c642b-d242-47bf-bdfc-91179e75305a

Wakeling, E.L., Amero, S.A., Alders, M., Bliek, J., Forsythe, E., Kumar, S., Lim, D.H., MacDonald, F., Mackay, D.J., Maher, E.R., Moore, G.E., Poole, R.L., Price, S.M., Tangeraas, T., Turner, C.L.S., Van Haelst, M.M., Willoughby, C., Temple, I.K. and Cobben, J.M. (2010) Epigenotype-phenotype correlations in Silver-Russell syndrome. Journal of Medical Genetics, 47 (11), 760-768. (doi:10.1136/jmg.2010.079111). (PMID:20685669)

Record type: Article

Abstract

Background Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in 5-10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information on the condition. Methods A detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44) was undertaken. Results and conclusions The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation was more likely to be scored as 'classical' SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. The authors report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings, although recurrence risk remains low in the majority of cases. Overall, a wide range of severity was observed, particularly with ICR1 hypomethylation. A low threshold for investigation of patients with features suggestive, but not typical, of SRS is therefore recommended.

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Accepted/In Press date: 3 August 2010
Published date: November 2010
Organisations: Human Genetics

Identifiers

Local EPrints ID: 162267
URI: http://eprints.soton.ac.uk/id/eprint/162267
ISSN: 0022-2593
PURE UUID: c10a94e3-2de5-4442-92f1-ec06c656aaed
ORCID for D.J. Mackay: ORCID iD orcid.org/0000-0003-3088-4401
ORCID for I.K. Temple: ORCID iD orcid.org/0000-0002-6045-1781

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Date deposited: 17 Aug 2010 16:36
Last modified: 26 Nov 2019 01:55

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Contributors

Author: E.L. Wakeling
Author: S.A. Amero
Author: M. Alders
Author: J. Bliek
Author: E. Forsythe
Author: S. Kumar
Author: D.H. Lim
Author: F. MacDonald
Author: D.J. Mackay ORCID iD
Author: E.R. Maher
Author: G.E. Moore
Author: R.L. Poole
Author: S.M. Price
Author: T. Tangeraas
Author: C.L.S. Turner
Author: M.M. Van Haelst
Author: C. Willoughby
Author: I.K. Temple ORCID iD
Author: J.M. Cobben

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