Cargando…

DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes

The additional sex combs-like (ASXL) gene family—encoded by ASXL1, ASXL2, and ASXL3—is crucial for mammalian development. Pathogenic variants in the ASXL gene family are associated with three phenotypically distinct neurodevelopmental syndromes. Our previous work has shown that syndromic conditions...

Descripción completa

Detalles Bibliográficos
Autores principales: Awamleh, Zain, Chater-Diehl, Eric, Choufani, Sanaa, Wei, Elizabeth, Kianmahd, Rebecca R., Yu, Anna, Chad, Lauren, Costain, Gregory, Tan, Wen-Hann, Scherer, Stephen W., Arboleda, Valerie A., Russell, Bianca E., Weksberg, Rosanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177544/
https://www.ncbi.nlm.nih.gov/pubmed/35361921
http://dx.doi.org/10.1038/s41431-022-01083-0
_version_ 1784722904719556608
author Awamleh, Zain
Chater-Diehl, Eric
Choufani, Sanaa
Wei, Elizabeth
Kianmahd, Rebecca R.
Yu, Anna
Chad, Lauren
Costain, Gregory
Tan, Wen-Hann
Scherer, Stephen W.
Arboleda, Valerie A.
Russell, Bianca E.
Weksberg, Rosanna
author_facet Awamleh, Zain
Chater-Diehl, Eric
Choufani, Sanaa
Wei, Elizabeth
Kianmahd, Rebecca R.
Yu, Anna
Chad, Lauren
Costain, Gregory
Tan, Wen-Hann
Scherer, Stephen W.
Arboleda, Valerie A.
Russell, Bianca E.
Weksberg, Rosanna
author_sort Awamleh, Zain
collection PubMed
description The additional sex combs-like (ASXL) gene family—encoded by ASXL1, ASXL2, and ASXL3—is crucial for mammalian development. Pathogenic variants in the ASXL gene family are associated with three phenotypically distinct neurodevelopmental syndromes. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show consistent patterns of genome-wide DNA methylation (DNAm) alterations, i.e., DNAm signatures in peripheral blood. Given the role of ASXL1 in chromatin modification, we hypothesized that pathogenic ASXL1 variants underlying Bohring-Opitz syndrome (BOS) have a unique DNAm signature. We profiled whole-blood DNAm for 17 ASXL1 variants, and 35 sex- and age-matched typically developing individuals, using Illumina’s Infinium EPIC array. We identified 763 differentially methylated CpG sites in individuals with BOS. Differentially methylated sites overlapped 323 unique genes, including HOXA5 and HOXB4, supporting the functional relevance of DNAm signatures. We used a machine-learning classification model based on the BOS DNAm signature to classify variants of uncertain significance in ASXL1, as well as pathogenic ASXL2 and ASXL3 variants. The DNAm profile of one individual with the ASXL2 variant was BOS-like, whereas the DNAm profiles of three individuals with ASXL3 variants were control-like. We also used Horvath’s epigenetic clock, which showed acceleration in DNAm age in individuals with pathogenic ASXL1 variants, and the individual with the pathogenic ASXL2 variant, but not in individuals with ASXL3 variants. These studies enhance our understanding of the epigenetic dysregulation underpinning ASXL gene family-associated syndromes.
format Online
Article
Text
id pubmed-9177544
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Springer International Publishing
record_format MEDLINE/PubMed
spelling pubmed-91775442022-06-10 DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes Awamleh, Zain Chater-Diehl, Eric Choufani, Sanaa Wei, Elizabeth Kianmahd, Rebecca R. Yu, Anna Chad, Lauren Costain, Gregory Tan, Wen-Hann Scherer, Stephen W. Arboleda, Valerie A. Russell, Bianca E. Weksberg, Rosanna Eur J Hum Genet Article The additional sex combs-like (ASXL) gene family—encoded by ASXL1, ASXL2, and ASXL3—is crucial for mammalian development. Pathogenic variants in the ASXL gene family are associated with three phenotypically distinct neurodevelopmental syndromes. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show consistent patterns of genome-wide DNA methylation (DNAm) alterations, i.e., DNAm signatures in peripheral blood. Given the role of ASXL1 in chromatin modification, we hypothesized that pathogenic ASXL1 variants underlying Bohring-Opitz syndrome (BOS) have a unique DNAm signature. We profiled whole-blood DNAm for 17 ASXL1 variants, and 35 sex- and age-matched typically developing individuals, using Illumina’s Infinium EPIC array. We identified 763 differentially methylated CpG sites in individuals with BOS. Differentially methylated sites overlapped 323 unique genes, including HOXA5 and HOXB4, supporting the functional relevance of DNAm signatures. We used a machine-learning classification model based on the BOS DNAm signature to classify variants of uncertain significance in ASXL1, as well as pathogenic ASXL2 and ASXL3 variants. The DNAm profile of one individual with the ASXL2 variant was BOS-like, whereas the DNAm profiles of three individuals with ASXL3 variants were control-like. We also used Horvath’s epigenetic clock, which showed acceleration in DNAm age in individuals with pathogenic ASXL1 variants, and the individual with the pathogenic ASXL2 variant, but not in individuals with ASXL3 variants. These studies enhance our understanding of the epigenetic dysregulation underpinning ASXL gene family-associated syndromes. Springer International Publishing 2022-04-01 2022-06 /pmc/articles/PMC9177544/ /pubmed/35361921 http://dx.doi.org/10.1038/s41431-022-01083-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Awamleh, Zain
Chater-Diehl, Eric
Choufani, Sanaa
Wei, Elizabeth
Kianmahd, Rebecca R.
Yu, Anna
Chad, Lauren
Costain, Gregory
Tan, Wen-Hann
Scherer, Stephen W.
Arboleda, Valerie A.
Russell, Bianca E.
Weksberg, Rosanna
DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes
title DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes
title_full DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes
title_fullStr DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes
title_full_unstemmed DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes
title_short DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes
title_sort dna methylation signature associated with bohring-opitz syndrome: a new tool for functional classification of variants in asxl genes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177544/
https://www.ncbi.nlm.nih.gov/pubmed/35361921
http://dx.doi.org/10.1038/s41431-022-01083-0
work_keys_str_mv AT awamlehzain dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes
AT chaterdiehleric dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes
AT choufanisanaa dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes
AT weielizabeth dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes
AT kianmahdrebeccar dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes
AT yuanna dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes
AT chadlauren dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes
AT costaingregory dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes
AT tanwenhann dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes
AT schererstephenw dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes
AT arboledavaleriea dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes
AT russellbiancae dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes
AT weksbergrosanna dnamethylationsignatureassociatedwithbohringopitzsyndromeanewtoolforfunctionalclassificationofvariantsinasxlgenes