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Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders
BACKGROUND: Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype dat...
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/PMC6366120/ https://www.ncbi.nlm.nih.gov/pubmed/30732576 http://dx.doi.org/10.1186/s11689-019-9263-3 |
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author | Costain, Gregory Walker, Susan Argiropoulos, Bob Baribeau, Danielle A. Bassett, Anne S. Boot, Erik Devriendt, Koen Kellam, Barbara Marshall, Christian R. Prasad, Aparna Serrano, Moises A. Stavropoulos, D. James Twede, Hope Vermeesch, Joris R. Vorstman, Jacob A. S. Scherer, Stephen W. |
author_facet | Costain, Gregory Walker, Susan Argiropoulos, Bob Baribeau, Danielle A. Bassett, Anne S. Boot, Erik Devriendt, Koen Kellam, Barbara Marshall, Christian R. Prasad, Aparna Serrano, Moises A. Stavropoulos, D. James Twede, Hope Vermeesch, Joris R. Vorstman, Jacob A. S. Scherer, Stephen W. |
author_sort | Costain, Gregory |
collection | PubMed |
description | BACKGROUND: Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs. METHODS: We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases. RESULTS: We identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs. CONCLUSIONS: Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data. |
format | Online Article Text |
id | pubmed-6366120 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-63661202019-02-15 Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders Costain, Gregory Walker, Susan Argiropoulos, Bob Baribeau, Danielle A. Bassett, Anne S. Boot, Erik Devriendt, Koen Kellam, Barbara Marshall, Christian R. Prasad, Aparna Serrano, Moises A. Stavropoulos, D. James Twede, Hope Vermeesch, Joris R. Vorstman, Jacob A. S. Scherer, Stephen W. J Neurodev Disord Research BACKGROUND: Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs. METHODS: We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases. RESULTS: We identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs. CONCLUSIONS: Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data. BioMed Central 2019-02-07 /pmc/articles/PMC6366120/ /pubmed/30732576 http://dx.doi.org/10.1186/s11689-019-9263-3 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 Costain, Gregory Walker, Susan Argiropoulos, Bob Baribeau, Danielle A. Bassett, Anne S. Boot, Erik Devriendt, Koen Kellam, Barbara Marshall, Christian R. Prasad, Aparna Serrano, Moises A. Stavropoulos, D. James Twede, Hope Vermeesch, Joris R. Vorstman, Jacob A. S. Scherer, Stephen W. Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders |
title | Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders |
title_full | Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders |
title_fullStr | Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders |
title_full_unstemmed | Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders |
title_short | Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders |
title_sort | rare copy number variations affecting the synaptic gene dmxl2 in neurodevelopmental disorders |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366120/ https://www.ncbi.nlm.nih.gov/pubmed/30732576 http://dx.doi.org/10.1186/s11689-019-9263-3 |
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