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CNTNAP2 Heterozygous Missense Variants: Risk Factors for Autism Spectrum Disorder and/or Other Pathologies?
The CNTNAP2 gene has been proposed to be one of the major susceptibility genes for neurodevelopmental disorders, in which numerous heterozygous missense variants have been identified in patients with autism spectrum disorder (ASD). The contribution of these variants to the manifestations of ASD is h...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236484/ https://www.ncbi.nlm.nih.gov/pubmed/30450007 http://dx.doi.org/10.1177/1179069518809666 |
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author | Canali, Giorgia Goutebroze, Laurence |
author_facet | Canali, Giorgia Goutebroze, Laurence |
author_sort | Canali, Giorgia |
collection | PubMed |
description | The CNTNAP2 gene has been proposed to be one of the major susceptibility genes for neurodevelopmental disorders, in which numerous heterozygous missense variants have been identified in patients with autism spectrum disorder (ASD). The contribution of these variants to the manifestations of ASD is however highly controversial because numerous heterozygous missense variants have also been identified in control subjects. In a recent study, we set up a sensitive developmental in vitro cell assay to clarify the potential functional impact of these variants in a heterozygous Cntnap2 background relevant for CNTNAP2 heterozygosity in patients with ASD. We showed that the cell adhesion glycoprotein Caspr2 encoded by CNTNAP2 plays a dose-dependent role in cortical neuron axon growth and provided a proof of principle that some variants have functional consequences, either a loss of function or a dominant-negative effect. This indicates that phenotypes mimicking CNTNAP2 heterozygous and homozygous null mutation may exist in humans. Our observations further suggest that more variants than originally expected could be functionally deleterious and induce a high heterogeneity of phenotypes at the scale of the whole brain. This raises the interesting possibility that CNTNAP2 heterozygous missense variants could define an overall endophenotype shaping a risk for ASD and questions whether, beyond ASD, the variants could contribute to the development of other neurodevelopmental disorders and/or genetically less complex pathologies. |
format | Online Article Text |
id | pubmed-6236484 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-62364842018-11-16 CNTNAP2 Heterozygous Missense Variants: Risk Factors for Autism Spectrum Disorder and/or Other Pathologies? Canali, Giorgia Goutebroze, Laurence J Exp Neurosci Commentary The CNTNAP2 gene has been proposed to be one of the major susceptibility genes for neurodevelopmental disorders, in which numerous heterozygous missense variants have been identified in patients with autism spectrum disorder (ASD). The contribution of these variants to the manifestations of ASD is however highly controversial because numerous heterozygous missense variants have also been identified in control subjects. In a recent study, we set up a sensitive developmental in vitro cell assay to clarify the potential functional impact of these variants in a heterozygous Cntnap2 background relevant for CNTNAP2 heterozygosity in patients with ASD. We showed that the cell adhesion glycoprotein Caspr2 encoded by CNTNAP2 plays a dose-dependent role in cortical neuron axon growth and provided a proof of principle that some variants have functional consequences, either a loss of function or a dominant-negative effect. This indicates that phenotypes mimicking CNTNAP2 heterozygous and homozygous null mutation may exist in humans. Our observations further suggest that more variants than originally expected could be functionally deleterious and induce a high heterogeneity of phenotypes at the scale of the whole brain. This raises the interesting possibility that CNTNAP2 heterozygous missense variants could define an overall endophenotype shaping a risk for ASD and questions whether, beyond ASD, the variants could contribute to the development of other neurodevelopmental disorders and/or genetically less complex pathologies. SAGE Publications 2018-11-09 /pmc/articles/PMC6236484/ /pubmed/30450007 http://dx.doi.org/10.1177/1179069518809666 Text en © The Author(s) 2018 http://www.creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Commentary Canali, Giorgia Goutebroze, Laurence CNTNAP2 Heterozygous Missense Variants: Risk Factors for Autism Spectrum Disorder and/or Other Pathologies? |
title | CNTNAP2 Heterozygous Missense Variants: Risk Factors
for Autism Spectrum Disorder and/or Other Pathologies? |
title_full | CNTNAP2 Heterozygous Missense Variants: Risk Factors
for Autism Spectrum Disorder and/or Other Pathologies? |
title_fullStr | CNTNAP2 Heterozygous Missense Variants: Risk Factors
for Autism Spectrum Disorder and/or Other Pathologies? |
title_full_unstemmed | CNTNAP2 Heterozygous Missense Variants: Risk Factors
for Autism Spectrum Disorder and/or Other Pathologies? |
title_short | CNTNAP2 Heterozygous Missense Variants: Risk Factors
for Autism Spectrum Disorder and/or Other Pathologies? |
title_sort | cntnap2 heterozygous missense variants: risk factors
for autism spectrum disorder and/or other pathologies? |
topic | Commentary |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236484/ https://www.ncbi.nlm.nih.gov/pubmed/30450007 http://dx.doi.org/10.1177/1179069518809666 |
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