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Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging
Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging
Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G>A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated to genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders; NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamentally new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance and determinants of biological aging in these growth disorders.
1088-9051
1057-1066
Jeffries, Aaron R.
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Maroofian, Reza
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Salter, Claire G.
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Chioza, Barry A.
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Cross, Harold E.
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Patton, Michael A.
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Dempster, Emma
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Temple, I. Karen
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Mackay, Deborah
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Rezwan, Faisal I.
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Aksglaede, Lise
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Baralle, Diana
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Dabir, Tabib
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Hunter, Matthew Frank
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Kamath, Arveen
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Kumar, Ajith
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Newbury-Ecob, Ruth
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Selicorni, Angelo
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Springer, Amanda
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van Maldergem, Lionel
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Varghese, Vinod
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Yachelevich, Naomi
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Tatton-Brown, Katrina
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Mill, Jonathan
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Crosby, Andrew H.
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Baple, Emma
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Jeffries, Aaron R.
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Maroofian, Reza
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Salter, Claire G.
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Chioza, Barry A.
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Cross, Harold E.
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Patton, Michael A.
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Dempster, Emma
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Temple, I. Karen
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Mackay, Deborah
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Rezwan, Faisal I.
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Aksglaede, Lise
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Baralle, Diana
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Dabir, Tabib
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Hunter, Matthew Frank
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Kamath, Arveen
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Kumar, Ajith
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Newbury-Ecob, Ruth
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Selicorni, Angelo
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Springer, Amanda
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van Maldergem, Lionel
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Varghese, Vinod
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Yachelevich, Naomi
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Tatton-Brown, Katrina
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Mill, Jonathan
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Crosby, Andrew H.
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Baple, Emma
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Jeffries, Aaron R., Maroofian, Reza, Salter, Claire G., Chioza, Barry A., Cross, Harold E., Patton, Michael A., Dempster, Emma, Temple, I. Karen, Mackay, Deborah, Rezwan, Faisal I., Aksglaede, Lise, Baralle, Diana, Dabir, Tabib, Hunter, Matthew Frank, Kamath, Arveen, Kumar, Ajith, Newbury-Ecob, Ruth, Selicorni, Angelo, Springer, Amanda, van Maldergem, Lionel, Varghese, Vinod, Yachelevich, Naomi, Tatton-Brown, Katrina, Mill, Jonathan, Crosby, Andrew H. and Baple, Emma (2019) Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging. Genome Research, 29 (7), 1057-1066. (doi:10.1101/gr.243584.118).

Record type: Article

Abstract

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G>A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated to genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders; NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamentally new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance and determinants of biological aging in these growth disorders.

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More information

Accepted/In Press date: 24 May 2019
e-pub ahead of print date: 3 June 2019
Published date: 1 July 2019

Identifiers

Local EPrints ID: 431912
URI: http://eprints.soton.ac.uk/id/eprint/431912
ISSN: 1088-9051
PURE UUID: 5cfcd046-e99d-416e-9d87-d3f13fdfd2d0
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781
ORCID for Deborah Mackay: ORCID iD orcid.org/0000-0003-3088-4401
ORCID for Faisal I. Rezwan: ORCID iD orcid.org/0000-0001-9921-222X
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

Catalogue record

Date deposited: 21 Jun 2019 16:30
Last modified: 26 Nov 2021 03:00

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Contributors

Author: Aaron R. Jeffries
Author: Reza Maroofian
Author: Claire G. Salter
Author: Barry A. Chioza
Author: Harold E. Cross
Author: Michael A. Patton
Author: Emma Dempster
Author: I. Karen Temple ORCID iD
Author: Deborah Mackay ORCID iD
Author: Faisal I. Rezwan ORCID iD
Author: Lise Aksglaede
Author: Diana Baralle ORCID iD
Author: Tabib Dabir
Author: Matthew Frank Hunter
Author: Arveen Kamath
Author: Ajith Kumar
Author: Ruth Newbury-Ecob
Author: Angelo Selicorni
Author: Amanda Springer
Author: Lionel van Maldergem
Author: Vinod Varghese
Author: Naomi Yachelevich
Author: Katrina Tatton-Brown
Author: Jonathan Mill
Author: Andrew H. Crosby
Author: Emma Baple

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