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Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome
BACKGROUND: ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in chromatin regulation. We hypothesized that the disruption of chromatin regulation might result i...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487024/ https://www.ncbi.nlm.nih.gov/pubmed/31029150 http://dx.doi.org/10.1186/s13148-019-0658-5 |
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author | Bend, Eric G. Aref-Eshghi, Erfan Everman, David B. Rogers, R. Curtis Cathey, Sara S. Prijoles, Eloise J. Lyons, Michael J. Davis, Heather Clarkson, Katie Gripp, Karen W. Li, Dong Bhoj, Elizabeth Zackai, Elaine Mark, Paul Hakonarson, Hakon Demmer, Laurie A. Levy, Michael A. Kerkhof, Jennifer Stuart, Alan Rodenhiser, David Friez, Michael J. Stevenson, Roger E. Schwartz, Charles E. Sadikovic, Bekim |
author_facet | Bend, Eric G. Aref-Eshghi, Erfan Everman, David B. Rogers, R. Curtis Cathey, Sara S. Prijoles, Eloise J. Lyons, Michael J. Davis, Heather Clarkson, Katie Gripp, Karen W. Li, Dong Bhoj, Elizabeth Zackai, Elaine Mark, Paul Hakonarson, Hakon Demmer, Laurie A. Levy, Michael A. Kerkhof, Jennifer Stuart, Alan Rodenhiser, David Friez, Michael J. Stevenson, Roger E. Schwartz, Charles E. Sadikovic, Bekim |
author_sort | Bend, Eric G. |
collection | PubMed |
description | BACKGROUND: ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in chromatin regulation. We hypothesized that the disruption of chromatin regulation might result in specific DNA methylation patterns that could be used in the molecular diagnosis of ADNP syndrome. RESULTS: We identified two distinct and partially opposing genomic DNA methylation episignatures in the peripheral blood samples from 22 patients with ADNP syndrome. The “epi-ADNP-1” episignature included ~ 6000 mostly hypomethylated CpGs, and the “epi-ADNP-2” episignature included ~ 1000 predominantly hypermethylated CpGs. The two signatures correlated with the locations of the ADNP mutations. Epi-ADNP-1 mutations occupy the N- and C-terminus, and epi-ADNP-2 mutations are centered on the nuclear localization signal. The episignatures were enriched for genes involved in neuronal system development and function. A classifier trained on these profiles yielded full sensitivity and specificity in detecting patients with either of the two episignatures. Applying this model to seven patients with uncertain clinical diagnosis enabled reclassification of genetic variants of uncertain significance and assigned new diagnosis when the primary clinical suspicion was not correct. When applied to a large cohort of unresolved patients with developmental delay (N = 1150), the model predicted three additional previously undiagnosed patients to have ADNP syndrome. DNA sequencing of these subjects, wherever available, identified pathogenic mutations within the gene domains predicted by the model. CONCLUSIONS: We describe the first Mendelian condition with two distinct episignatures caused by mutations in a single gene. These highly sensitive and specific DNA methylation episignatures enable diagnosis, screening, and genetic variant classifications in ADNP syndrome. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13148-019-0658-5) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6487024 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-64870242019-05-06 Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome Bend, Eric G. Aref-Eshghi, Erfan Everman, David B. Rogers, R. Curtis Cathey, Sara S. Prijoles, Eloise J. Lyons, Michael J. Davis, Heather Clarkson, Katie Gripp, Karen W. Li, Dong Bhoj, Elizabeth Zackai, Elaine Mark, Paul Hakonarson, Hakon Demmer, Laurie A. Levy, Michael A. Kerkhof, Jennifer Stuart, Alan Rodenhiser, David Friez, Michael J. Stevenson, Roger E. Schwartz, Charles E. Sadikovic, Bekim Clin Epigenetics Research BACKGROUND: ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in chromatin regulation. We hypothesized that the disruption of chromatin regulation might result in specific DNA methylation patterns that could be used in the molecular diagnosis of ADNP syndrome. RESULTS: We identified two distinct and partially opposing genomic DNA methylation episignatures in the peripheral blood samples from 22 patients with ADNP syndrome. The “epi-ADNP-1” episignature included ~ 6000 mostly hypomethylated CpGs, and the “epi-ADNP-2” episignature included ~ 1000 predominantly hypermethylated CpGs. The two signatures correlated with the locations of the ADNP mutations. Epi-ADNP-1 mutations occupy the N- and C-terminus, and epi-ADNP-2 mutations are centered on the nuclear localization signal. The episignatures were enriched for genes involved in neuronal system development and function. A classifier trained on these profiles yielded full sensitivity and specificity in detecting patients with either of the two episignatures. Applying this model to seven patients with uncertain clinical diagnosis enabled reclassification of genetic variants of uncertain significance and assigned new diagnosis when the primary clinical suspicion was not correct. When applied to a large cohort of unresolved patients with developmental delay (N = 1150), the model predicted three additional previously undiagnosed patients to have ADNP syndrome. DNA sequencing of these subjects, wherever available, identified pathogenic mutations within the gene domains predicted by the model. CONCLUSIONS: We describe the first Mendelian condition with two distinct episignatures caused by mutations in a single gene. These highly sensitive and specific DNA methylation episignatures enable diagnosis, screening, and genetic variant classifications in ADNP syndrome. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13148-019-0658-5) contains supplementary material, which is available to authorized users. BioMed Central 2019-04-27 /pmc/articles/PMC6487024/ /pubmed/31029150 http://dx.doi.org/10.1186/s13148-019-0658-5 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Bend, Eric G. Aref-Eshghi, Erfan Everman, David B. Rogers, R. Curtis Cathey, Sara S. Prijoles, Eloise J. Lyons, Michael J. Davis, Heather Clarkson, Katie Gripp, Karen W. Li, Dong Bhoj, Elizabeth Zackai, Elaine Mark, Paul Hakonarson, Hakon Demmer, Laurie A. Levy, Michael A. Kerkhof, Jennifer Stuart, Alan Rodenhiser, David Friez, Michael J. Stevenson, Roger E. Schwartz, Charles E. Sadikovic, Bekim Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome |
title | Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome |
title_full | Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome |
title_fullStr | Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome |
title_full_unstemmed | Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome |
title_short | Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome |
title_sort | gene domain-specific dna methylation episignatures highlight distinct molecular entities of adnp syndrome |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487024/ https://www.ncbi.nlm.nih.gov/pubmed/31029150 http://dx.doi.org/10.1186/s13148-019-0658-5 |
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