Understanding rare variant contributions to autism: lessons from dystrophin-deficient model
Abstract Duchenne and Becker Muscular Dystrophy are dystrophinopathies with a prevalence of 1:5000–6000 males, caused by pathogenic variants in DMD. These conditions are often accompanied by neurodevelopmental disorders (NDDs) like autism (ASD; ~20%) and intellectual disability (ID; ~30%). However,...
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Nature Portfolio
2025-03-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-025-00469-5 |
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| author | Claudia Ismania Samogy Costa Luciana Madanelo Jaqueline Yu Ting Wang Gabriele da Silva Campos Ana Cristina De Sanctis Girardi Marília Scliar Frederico Monfardini Rita de Cássia Mingroni Pavanello Vivian Romanholi Cória Maria Dulcetti Vibranovski Ana Cristina Krepischi Naila Cristina Vilaça Lourenço Mayana Zatz Guilherme Lopes Yamamoto Elaine Cristina Zachi Maria Rita Passos-Bueno |
| author_facet | Claudia Ismania Samogy Costa Luciana Madanelo Jaqueline Yu Ting Wang Gabriele da Silva Campos Ana Cristina De Sanctis Girardi Marília Scliar Frederico Monfardini Rita de Cássia Mingroni Pavanello Vivian Romanholi Cória Maria Dulcetti Vibranovski Ana Cristina Krepischi Naila Cristina Vilaça Lourenço Mayana Zatz Guilherme Lopes Yamamoto Elaine Cristina Zachi Maria Rita Passos-Bueno |
| author_sort | Claudia Ismania Samogy Costa |
| collection | DOAJ |
| description | Abstract Duchenne and Becker Muscular Dystrophy are dystrophinopathies with a prevalence of 1:5000–6000 males, caused by pathogenic variants in DMD. These conditions are often accompanied by neurodevelopmental disorders (NDDs) like autism (ASD; ~20%) and intellectual disability (ID; ~30%). However, their low penetrance in dystrophinopathies suggests additional contributing factors. In our study, 83 individuals with dystrophinopathies were clinically evaluated and categorized based on ASD (36 individuals), ID risk (12 individuals), or controls (35 individuals). Exome sequencing analysis revealed an enrichment of risk de novo variants (DNVs) in ASD-DMD individuals (adjusted p value = 0.0356), with the number of DNVs correlating with paternal age (p value = 0.0133). Additionally, DMD-ASD individuals showed a higher average of rare risk variants (RRVs) compared to DMD-Controls (adjusted p value = 0.0285). Gene ontology analysis revealed an enrichment of extracellular matrix-related genes, especially collagens, and Ehlers-Danlos syndrome genes in ASD-DMD and DMD-ID groups. These findings support an oligogenic model for ASD in dystrophinopathies, highlighting the importance of investigating homogenized samples to elucidate ASD’s genetic architecture. |
| format | Article |
| id | doaj-art-541e365468534eefac5cdd82c700bf32 |
| institution | DOAJ |
| issn | 2056-7944 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Genomic Medicine |
| spelling | doaj-art-541e365468534eefac5cdd82c700bf322025-08-20T02:47:07ZengNature Portfolionpj Genomic Medicine2056-79442025-03-0110111210.1038/s41525-025-00469-5Understanding rare variant contributions to autism: lessons from dystrophin-deficient modelClaudia Ismania Samogy Costa0Luciana Madanelo1Jaqueline Yu Ting Wang2Gabriele da Silva Campos3Ana Cristina De Sanctis Girardi4Marília Scliar5Frederico Monfardini6Rita de Cássia Mingroni Pavanello7Vivian Romanholi Cória8Maria Dulcetti Vibranovski9Ana Cristina Krepischi10Naila Cristina Vilaça Lourenço11Mayana Zatz12Guilherme Lopes Yamamoto13Elaine Cristina Zachi14Maria Rita Passos-Bueno15Departamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloDepartamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São PauloAbstract Duchenne and Becker Muscular Dystrophy are dystrophinopathies with a prevalence of 1:5000–6000 males, caused by pathogenic variants in DMD. These conditions are often accompanied by neurodevelopmental disorders (NDDs) like autism (ASD; ~20%) and intellectual disability (ID; ~30%). However, their low penetrance in dystrophinopathies suggests additional contributing factors. In our study, 83 individuals with dystrophinopathies were clinically evaluated and categorized based on ASD (36 individuals), ID risk (12 individuals), or controls (35 individuals). Exome sequencing analysis revealed an enrichment of risk de novo variants (DNVs) in ASD-DMD individuals (adjusted p value = 0.0356), with the number of DNVs correlating with paternal age (p value = 0.0133). Additionally, DMD-ASD individuals showed a higher average of rare risk variants (RRVs) compared to DMD-Controls (adjusted p value = 0.0285). Gene ontology analysis revealed an enrichment of extracellular matrix-related genes, especially collagens, and Ehlers-Danlos syndrome genes in ASD-DMD and DMD-ID groups. These findings support an oligogenic model for ASD in dystrophinopathies, highlighting the importance of investigating homogenized samples to elucidate ASD’s genetic architecture.https://doi.org/10.1038/s41525-025-00469-5 |
| spellingShingle | Claudia Ismania Samogy Costa Luciana Madanelo Jaqueline Yu Ting Wang Gabriele da Silva Campos Ana Cristina De Sanctis Girardi Marília Scliar Frederico Monfardini Rita de Cássia Mingroni Pavanello Vivian Romanholi Cória Maria Dulcetti Vibranovski Ana Cristina Krepischi Naila Cristina Vilaça Lourenço Mayana Zatz Guilherme Lopes Yamamoto Elaine Cristina Zachi Maria Rita Passos-Bueno Understanding rare variant contributions to autism: lessons from dystrophin-deficient model npj Genomic Medicine |
| title | Understanding rare variant contributions to autism: lessons from dystrophin-deficient model |
| title_full | Understanding rare variant contributions to autism: lessons from dystrophin-deficient model |
| title_fullStr | Understanding rare variant contributions to autism: lessons from dystrophin-deficient model |
| title_full_unstemmed | Understanding rare variant contributions to autism: lessons from dystrophin-deficient model |
| title_short | Understanding rare variant contributions to autism: lessons from dystrophin-deficient model |
| title_sort | understanding rare variant contributions to autism lessons from dystrophin deficient model |
| url | https://doi.org/10.1038/s41525-025-00469-5 |
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