Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
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
_version_ 1783393556628504576
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
work_keys_str_mv AT costaingregory rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT walkersusan rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT argiropoulosbob rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT baribeaudaniellea rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT bassettannes rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT booterik rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT devriendtkoen rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT kellambarbara rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT marshallchristianr rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT prasadaparna rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT serranomoisesa rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT stavropoulosdjames rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT twedehope rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT vermeeschjorisr rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT vorstmanjacobas rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders
AT schererstephenw rarecopynumbervariationsaffectingthesynapticgenedmxl2inneurodevelopmentaldisorders