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Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders

Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders
Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders
Imprinting disorders are associated with mutations and epimutations affecting imprinted genes, that is those whose expression is restricted by parent of origin. Their diagnosis is challenging for two reasons: firstly, their clinical features, particularly prenatal and postnatal growth disturbance, are heterogeneous and partially overlapping; secondly, their underlying molecular defects include mutation, epimutation, copy number variation, and chromosomal errors, and can be further complicated by somatic mosaicism and multi-locus methylation defects. It is currently unclear to what extent the observed phenotypic heterogeneity reflects the underlying molecular pathophysiology; in particular, the molecular and clinical diversity of multilocus methylation defects remains uncertain. To address these issues we performed comprehensive methylation analysis of imprinted genes in a research cohort of 285 patients with clinical features of imprinting disorders, with or without a positive molecular diagnosis. 20 of 91 patients (22%) with diagnosed epimutations had methylation defects of additional imprinted loci, and the frequency of developmental delay and congenital anomalies was higher among these patients than those with isolated epimutations, indicating that hypomethylation of multiple imprinted loci is associated with increased diversity of clinical presentation. Among 194 patients with clinical features of an imprinting disorder but no molecular diagnosis, we found 15 (8%) with methylation anomalies, including missed and unexpected molecular diagnoses. These observations broaden the phenotypic and epigenetic definitions of imprinting disorders, and show the importance of comprehensive molecular testing for patient diagnosis and management.
DNA methylation, imprinting disorder, beckwith–wiedemann syndrome, silver–russell syndrome, transient neonatal diabetes, upd14 mat, wang syndrome, pseudohypoparathyroidism type 1B, angelman syndrome, prader willi syndrome
1552-4825
2174-2182
Poole, Rebecca L.
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Docherty, Louise E.
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Al Sayegh, Abeer
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Caliebe, Almuth
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Turner, Claire
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Baple, Emma
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Wakeling, Emma
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Harrison, Lucy
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Lehmann, Anna
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Temple, I. Karen
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Mackay, Deborah J.G.
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Poole, Rebecca L.
d8fe00fa-9deb-4a34-a7d8-4b7f57ce82fa
Docherty, Louise E.
4accb565-e53b-400f-8d62-83935e2ae410
Al Sayegh, Abeer
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Caliebe, Almuth
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Turner, Claire
2851c9ac-60b5-4f55-a9f7-54f9ce5de791
Baple, Emma
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Wakeling, Emma
b1b01d04-e571-4d6d-af7a-d9a2f61d975d
Harrison, Lucy
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Lehmann, Anna
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Temple, I. Karen
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Mackay, Deborah J.G.
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Poole, Rebecca L., Docherty, Louise E., Al Sayegh, Abeer, Caliebe, Almuth, Turner, Claire, Baple, Emma, Wakeling, Emma, Harrison, Lucy, Lehmann, Anna, Temple, I. Karen and Mackay, Deborah J.G. (2013) Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders. American Journal of Medical Genetics part A, 161 (9), 2174-2182. (doi:10.1002/ajmg.a.36049). (PMID:23913548)

Record type: Article

Abstract

Imprinting disorders are associated with mutations and epimutations affecting imprinted genes, that is those whose expression is restricted by parent of origin. Their diagnosis is challenging for two reasons: firstly, their clinical features, particularly prenatal and postnatal growth disturbance, are heterogeneous and partially overlapping; secondly, their underlying molecular defects include mutation, epimutation, copy number variation, and chromosomal errors, and can be further complicated by somatic mosaicism and multi-locus methylation defects. It is currently unclear to what extent the observed phenotypic heterogeneity reflects the underlying molecular pathophysiology; in particular, the molecular and clinical diversity of multilocus methylation defects remains uncertain. To address these issues we performed comprehensive methylation analysis of imprinted genes in a research cohort of 285 patients with clinical features of imprinting disorders, with or without a positive molecular diagnosis. 20 of 91 patients (22%) with diagnosed epimutations had methylation defects of additional imprinted loci, and the frequency of developmental delay and congenital anomalies was higher among these patients than those with isolated epimutations, indicating that hypomethylation of multiple imprinted loci is associated with increased diversity of clinical presentation. Among 194 patients with clinical features of an imprinting disorder but no molecular diagnosis, we found 15 (8%) with methylation anomalies, including missed and unexpected molecular diagnoses. These observations broaden the phenotypic and epigenetic definitions of imprinting disorders, and show the importance of comprehensive molecular testing for patient diagnosis and management.

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Published date: 2 August 2013
Keywords: DNA methylation, imprinting disorder, beckwith–wiedemann syndrome, silver–russell syndrome, transient neonatal diabetes, upd14 mat, wang syndrome, pseudohypoparathyroidism type 1B, angelman syndrome, prader willi syndrome
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 355690
URI: http://eprints.soton.ac.uk/id/eprint/355690
ISSN: 1552-4825
PURE UUID: c8258926-878e-4928-be2a-4f63884beaa3
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781
ORCID for Deborah J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

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Date deposited: 03 Sep 2013 15:29
Last modified: 28 Oct 2023 01:44

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Contributors

Author: Rebecca L. Poole
Author: Louise E. Docherty
Author: Abeer Al Sayegh
Author: Almuth Caliebe
Author: Claire Turner
Author: Emma Baple
Author: Emma Wakeling
Author: Lucy Harrison
Author: Anna Lehmann
Author: I. Karen Temple ORCID iD

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