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Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study
BACKGROUND: The relationships between specific genetic aetiology and phenotype in neurodevelopmental disorders are complex and hotly contested. Genes associated with intellectual disability (ID) can be grouped into networks according to gene function. This study explored whether individuals with ID...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731560/ https://www.ncbi.nlm.nih.gov/pubmed/33308299 http://dx.doi.org/10.1186/s13229-020-00403-9 |
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author | Brkić, Diandra Ng-Cordell, Elise O’Brien, Sinéad Scerif, Gaia Astle, Duncan Baker, Kate |
author_facet | Brkić, Diandra Ng-Cordell, Elise O’Brien, Sinéad Scerif, Gaia Astle, Duncan Baker, Kate |
author_sort | Brkić, Diandra |
collection | PubMed |
description | BACKGROUND: The relationships between specific genetic aetiology and phenotype in neurodevelopmental disorders are complex and hotly contested. Genes associated with intellectual disability (ID) can be grouped into networks according to gene function. This study explored whether individuals with ID show differences in autism spectrum characteristics (ASC), depending on the functional network membership of their rare, pathogenic de novo genetic variants. METHODS: Children and young people with ID of known genetic origin were allocated to two broad functional network groups: synaptic physiology (n = 29) or chromatin regulation (n = 23). We applied principle components analysis to the Social Responsiveness Scale to map the structure of ASC in this population and identified three components—Inflexibility, Social Understanding and Social Motivation. We then used Akaike information criterion to test the best fitting models for predicting ASC components, including demographic factors (age, gender), non-ASC behavioural factors (global adaptive function, anxiety, hyperactivity, inattention), and gene functional networks. RESULTS: We found that, when other factors are accounted for, the chromatin regulation group showed higher levels of Inflexibility. We also observed contrasting predictors of ASC within each network group. Within the chromatin regulation group, Social Understanding was associated with inattention, and Social Motivation was predicted by hyperactivity. Within the synaptic group, Social Understanding was associated with hyperactivity, and Social Motivation was linked to anxiety. LIMITATIONS: Functional network definitions were manually curated based on multiple sources of evidence, but a data-driven approach to classification may be more robust. Sample sizes for rare genetic diagnoses remain small, mitigated by our network-based approach to group comparisons. This is a cross-sectional study across a wide age range, and longitudinal data within focused age groups will be informative of developmental trajectories across network groups. CONCLUSION: We report that gene functional networks can predict Inflexibility, but not other ASC dimensions. Contrasting behavioural associations within each group suggest network-specific developmental pathways from genomic variation to autism. Simple classification of neurodevelopmental disorder genes as high risk or low risk for autism is unlikely to be valid or useful. |
format | Online Article Text |
id | pubmed-7731560 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-77315602020-12-15 Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study Brkić, Diandra Ng-Cordell, Elise O’Brien, Sinéad Scerif, Gaia Astle, Duncan Baker, Kate Mol Autism Research BACKGROUND: The relationships between specific genetic aetiology and phenotype in neurodevelopmental disorders are complex and hotly contested. Genes associated with intellectual disability (ID) can be grouped into networks according to gene function. This study explored whether individuals with ID show differences in autism spectrum characteristics (ASC), depending on the functional network membership of their rare, pathogenic de novo genetic variants. METHODS: Children and young people with ID of known genetic origin were allocated to two broad functional network groups: synaptic physiology (n = 29) or chromatin regulation (n = 23). We applied principle components analysis to the Social Responsiveness Scale to map the structure of ASC in this population and identified three components—Inflexibility, Social Understanding and Social Motivation. We then used Akaike information criterion to test the best fitting models for predicting ASC components, including demographic factors (age, gender), non-ASC behavioural factors (global adaptive function, anxiety, hyperactivity, inattention), and gene functional networks. RESULTS: We found that, when other factors are accounted for, the chromatin regulation group showed higher levels of Inflexibility. We also observed contrasting predictors of ASC within each network group. Within the chromatin regulation group, Social Understanding was associated with inattention, and Social Motivation was predicted by hyperactivity. Within the synaptic group, Social Understanding was associated with hyperactivity, and Social Motivation was linked to anxiety. LIMITATIONS: Functional network definitions were manually curated based on multiple sources of evidence, but a data-driven approach to classification may be more robust. Sample sizes for rare genetic diagnoses remain small, mitigated by our network-based approach to group comparisons. This is a cross-sectional study across a wide age range, and longitudinal data within focused age groups will be informative of developmental trajectories across network groups. CONCLUSION: We report that gene functional networks can predict Inflexibility, but not other ASC dimensions. Contrasting behavioural associations within each group suggest network-specific developmental pathways from genomic variation to autism. Simple classification of neurodevelopmental disorder genes as high risk or low risk for autism is unlikely to be valid or useful. BioMed Central 2020-12-11 /pmc/articles/PMC7731560/ /pubmed/33308299 http://dx.doi.org/10.1186/s13229-020-00403-9 Text en © The Author(s) 2020 Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data. |
spellingShingle | Research Brkić, Diandra Ng-Cordell, Elise O’Brien, Sinéad Scerif, Gaia Astle, Duncan Baker, Kate Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study |
title | Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study |
title_full | Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study |
title_fullStr | Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study |
title_full_unstemmed | Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study |
title_short | Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study |
title_sort | gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731560/ https://www.ncbi.nlm.nih.gov/pubmed/33308299 http://dx.doi.org/10.1186/s13229-020-00403-9 |
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