Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism
Abstract Duplication 15q (dup15q) syndrome is a leading genetic cause of autism spectrum disorder, offering a key model for studying autism-related mechanisms. Using single-cell and single-nucleus RNA sequencing of cortical organoids from dup15q patient-derived iPSCs and post-mortem brain samples, w...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61184-4 |
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| author | Yonatan Perez Dmitry Velmeshev Li Wang Matthew L. White Clara Siebert Jennifer Baltazar Guolong Zuo Juan Andrés Moriano Songcang Chen David M. Steffen Natalia Garcia Dutton Shaohui Wang Brittney Wick Maximilian Haeussler Stormy Chamberlain Arturo Alvarez-Buylla Arnold Kriegstein |
| author_facet | Yonatan Perez Dmitry Velmeshev Li Wang Matthew L. White Clara Siebert Jennifer Baltazar Guolong Zuo Juan Andrés Moriano Songcang Chen David M. Steffen Natalia Garcia Dutton Shaohui Wang Brittney Wick Maximilian Haeussler Stormy Chamberlain Arturo Alvarez-Buylla Arnold Kriegstein |
| author_sort | Yonatan Perez |
| collection | DOAJ |
| description | Abstract Duplication 15q (dup15q) syndrome is a leading genetic cause of autism spectrum disorder, offering a key model for studying autism-related mechanisms. Using single-cell and single-nucleus RNA sequencing of cortical organoids from dup15q patient-derived iPSCs and post-mortem brain samples, we identify increased glycolysis, disrupted layer-specific marker expression, and aberrant morphology in deep-layer neurons during fetal-stage organoid development. In adolescent-adult postmortem brains, upper-layer neurons exhibit heightened transcriptional burden related to synaptic signaling, a pattern shared with idiopathic autism. Using spatial transcriptomics, we confirm these cell-type-specific disruptions in brain tissue. By gene co-expression network analysis, we reveal disease-associated modules that are well preserved between postmortem and organoid samples, suggesting metabolic dysregulation that may lead to altered neuron projection, synaptic dysfunction, and neuron hyperexcitability in dup15q syndrome. |
| format | Article |
| id | doaj-art-a3b3a586454341ce8a22152004ea2d38 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a3b3a586454341ce8a22152004ea2d382025-08-20T03:37:37ZengNature PortfolioNature Communications2041-17232025-07-0116111610.1038/s41467-025-61184-4Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autismYonatan Perez0Dmitry Velmeshev1Li Wang2Matthew L. White3Clara Siebert4Jennifer Baltazar5Guolong Zuo6Juan Andrés Moriano7Songcang Chen8David M. Steffen9Natalia Garcia Dutton10Shaohui Wang11Brittney Wick12Maximilian Haeussler13Stormy Chamberlain14Arturo Alvarez-Buylla15Arnold Kriegstein16Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoGenomics Institute, University of CaliforniaGenomics Institute, University of CaliforniaDepartments of Genetics and Genome Sciences and Pediatrics, Connecticut Children’s Medical Center, University of Connecticut Health Center, 400 Farmington AvenueEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San FranciscoAbstract Duplication 15q (dup15q) syndrome is a leading genetic cause of autism spectrum disorder, offering a key model for studying autism-related mechanisms. Using single-cell and single-nucleus RNA sequencing of cortical organoids from dup15q patient-derived iPSCs and post-mortem brain samples, we identify increased glycolysis, disrupted layer-specific marker expression, and aberrant morphology in deep-layer neurons during fetal-stage organoid development. In adolescent-adult postmortem brains, upper-layer neurons exhibit heightened transcriptional burden related to synaptic signaling, a pattern shared with idiopathic autism. Using spatial transcriptomics, we confirm these cell-type-specific disruptions in brain tissue. By gene co-expression network analysis, we reveal disease-associated modules that are well preserved between postmortem and organoid samples, suggesting metabolic dysregulation that may lead to altered neuron projection, synaptic dysfunction, and neuron hyperexcitability in dup15q syndrome.https://doi.org/10.1038/s41467-025-61184-4 |
| spellingShingle | Yonatan Perez Dmitry Velmeshev Li Wang Matthew L. White Clara Siebert Jennifer Baltazar Guolong Zuo Juan Andrés Moriano Songcang Chen David M. Steffen Natalia Garcia Dutton Shaohui Wang Brittney Wick Maximilian Haeussler Stormy Chamberlain Arturo Alvarez-Buylla Arnold Kriegstein Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism Nature Communications |
| title | Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism |
| title_full | Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism |
| title_fullStr | Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism |
| title_full_unstemmed | Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism |
| title_short | Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism |
| title_sort | single cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism |
| url | https://doi.org/10.1038/s41467-025-61184-4 |
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