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Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene
Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability, although their underlying genetic factors are still largely unknown. Here we present a comprehensive genetic characterization of two ASD siblings from Sardinia by genome-wide copy number variation an...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406497/ https://www.ncbi.nlm.nih.gov/pubmed/30736458 http://dx.doi.org/10.3390/jcm8020212 |
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author | Bacchelli, Elena Loi, Eleonora Cameli, Cinzia Moi, Loredana Benedetti, Ana Florencia Vega Blois, Sylvain Fadda, Antonio Bonora, Elena Mattu, Sandra Fadda, Roberta Chessa, Rita Maestrini, Elena Doneddu, Giuseppe Zavattari, Patrizia |
author_facet | Bacchelli, Elena Loi, Eleonora Cameli, Cinzia Moi, Loredana Benedetti, Ana Florencia Vega Blois, Sylvain Fadda, Antonio Bonora, Elena Mattu, Sandra Fadda, Roberta Chessa, Rita Maestrini, Elena Doneddu, Giuseppe Zavattari, Patrizia |
author_sort | Bacchelli, Elena |
collection | PubMed |
description | Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability, although their underlying genetic factors are still largely unknown. Here we present a comprehensive genetic characterization of two ASD siblings from Sardinia by genome-wide copy number variation analysis and whole exome sequencing (WES), to identify novel genetic alterations associated with this disorder. Single nucleotide polymorphism (SNP) array data revealed a rare microdeletion involving CAPG, ELMOD3, and SH2D6 genes, in both siblings. CAPG encodes for a postsynaptic density (PSD) protein known to regulate spine morphogenesis and synaptic formation. The reduced CAPG mRNA and protein expression levels in ASD patients, in the presence of hemizygosity or a particular genetic and/or epigenetic background, highlighted the functional relevance of CAPG as a candidate gene for ASD. WES analysis led to the identification in both affected siblings of a rare frameshift mutation in VDAC3, a gene intolerant to loss of function mutation, encoding for a voltage-dependent anion channel localized on PSD. Moreover, four missense damaging variants were identified in genes intolerant to loss of function variation encoding for PSD proteins: PLXNA2, KCTD16, ARHGAP21, and SLC4A1. This study identifies CAPG and VDAC3 as candidate genes and provides additional support for genes encoding PSD proteins in ASD susceptibility. |
format | Online Article Text |
id | pubmed-6406497 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-64064972019-03-22 Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene Bacchelli, Elena Loi, Eleonora Cameli, Cinzia Moi, Loredana Benedetti, Ana Florencia Vega Blois, Sylvain Fadda, Antonio Bonora, Elena Mattu, Sandra Fadda, Roberta Chessa, Rita Maestrini, Elena Doneddu, Giuseppe Zavattari, Patrizia J Clin Med Article Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability, although their underlying genetic factors are still largely unknown. Here we present a comprehensive genetic characterization of two ASD siblings from Sardinia by genome-wide copy number variation analysis and whole exome sequencing (WES), to identify novel genetic alterations associated with this disorder. Single nucleotide polymorphism (SNP) array data revealed a rare microdeletion involving CAPG, ELMOD3, and SH2D6 genes, in both siblings. CAPG encodes for a postsynaptic density (PSD) protein known to regulate spine morphogenesis and synaptic formation. The reduced CAPG mRNA and protein expression levels in ASD patients, in the presence of hemizygosity or a particular genetic and/or epigenetic background, highlighted the functional relevance of CAPG as a candidate gene for ASD. WES analysis led to the identification in both affected siblings of a rare frameshift mutation in VDAC3, a gene intolerant to loss of function mutation, encoding for a voltage-dependent anion channel localized on PSD. Moreover, four missense damaging variants were identified in genes intolerant to loss of function variation encoding for PSD proteins: PLXNA2, KCTD16, ARHGAP21, and SLC4A1. This study identifies CAPG and VDAC3 as candidate genes and provides additional support for genes encoding PSD proteins in ASD susceptibility. MDPI 2019-02-07 /pmc/articles/PMC6406497/ /pubmed/30736458 http://dx.doi.org/10.3390/jcm8020212 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Bacchelli, Elena Loi, Eleonora Cameli, Cinzia Moi, Loredana Benedetti, Ana Florencia Vega Blois, Sylvain Fadda, Antonio Bonora, Elena Mattu, Sandra Fadda, Roberta Chessa, Rita Maestrini, Elena Doneddu, Giuseppe Zavattari, Patrizia Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene |
title | Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene |
title_full | Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene |
title_fullStr | Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene |
title_full_unstemmed | Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene |
title_short | Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene |
title_sort | analysis of a sardinian multiplex family with autism spectrum disorder points to post-synaptic density gene variants and identifies capg as a functionally relevant candidate gene |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406497/ https://www.ncbi.nlm.nih.gov/pubmed/30736458 http://dx.doi.org/10.3390/jcm8020212 |
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