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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By c...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530681/ https://www.ncbi.nlm.nih.gov/pubmed/33004838 http://dx.doi.org/10.1038/s41467-020-18723-y |
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author | Wang, Tianyun Hoekzema, Kendra Vecchio, Davide Wu, Huidan Sulovari, Arvis Coe, Bradley P. Gillentine, Madelyn A. Wilfert, Amy B. Perez-Jurado, Luis A. Kvarnung, Malin Sleyp, Yoeri Earl, Rachel K. Rosenfeld, Jill A. Geisheker, Madeleine R. Han, Lin Du, Bing Barnett, Chris Thompson, Elizabeth Shaw, Marie Carroll, Renee Friend, Kathryn Catford, Rachael Palmer, Elizabeth E. Zou, Xiaobing Ou, Jianjun Li, Honghui Guo, Hui Gerdts, Jennifer Avola, Emanuela Calabrese, Giuseppe Elia, Maurizio Greco, Donatella Lindstrand, Anna Nordgren, Ann Anderlid, Britt-Marie Vandeweyer, Geert Van Dijck, Anke Van der Aa, Nathalie McKenna, Brooke Hancarova, Miroslava Bendova, Sarka Havlovicova, Marketa Malerba, Giovanni Bernardina, Bernardo Dalla Muglia, Pierandrea van Haeringen, Arie Hoffer, Mariette J. V. Franke, Barbara Cappuccio, Gerarda Delatycki, Martin Lockhart, Paul J. Manning, Melanie A. Liu, Pengfei Scheffer, Ingrid E. Brunetti-Pierri, Nicola Rommelse, Nanda Amaral, David G. Santen, Gijs W. E. Trabetti, Elisabetta Sedláček, Zdeněk Michaelson, Jacob J. Pierce, Karen Courchesne, Eric Kooy, R. Frank Nordenskjöld, Magnus Romano, Corrado Peeters, Hilde Bernier, Raphael A. Gecz, Jozef Xia, Kun Eichler, Evan E. |
author_facet | Wang, Tianyun Hoekzema, Kendra Vecchio, Davide Wu, Huidan Sulovari, Arvis Coe, Bradley P. Gillentine, Madelyn A. Wilfert, Amy B. Perez-Jurado, Luis A. Kvarnung, Malin Sleyp, Yoeri Earl, Rachel K. Rosenfeld, Jill A. Geisheker, Madeleine R. Han, Lin Du, Bing Barnett, Chris Thompson, Elizabeth Shaw, Marie Carroll, Renee Friend, Kathryn Catford, Rachael Palmer, Elizabeth E. Zou, Xiaobing Ou, Jianjun Li, Honghui Guo, Hui Gerdts, Jennifer Avola, Emanuela Calabrese, Giuseppe Elia, Maurizio Greco, Donatella Lindstrand, Anna Nordgren, Ann Anderlid, Britt-Marie Vandeweyer, Geert Van Dijck, Anke Van der Aa, Nathalie McKenna, Brooke Hancarova, Miroslava Bendova, Sarka Havlovicova, Marketa Malerba, Giovanni Bernardina, Bernardo Dalla Muglia, Pierandrea van Haeringen, Arie Hoffer, Mariette J. V. Franke, Barbara Cappuccio, Gerarda Delatycki, Martin Lockhart, Paul J. Manning, Melanie A. Liu, Pengfei Scheffer, Ingrid E. Brunetti-Pierri, Nicola Rommelse, Nanda Amaral, David G. Santen, Gijs W. E. Trabetti, Elisabetta Sedláček, Zdeněk Michaelson, Jacob J. Pierce, Karen Courchesne, Eric Kooy, R. Frank Nordenskjöld, Magnus Romano, Corrado Peeters, Hilde Bernier, Raphael A. Gecz, Jozef Xia, Kun Eichler, Evan E. |
author_sort | Wang, Tianyun |
collection | PubMed |
description | Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort. |
format | Online Article Text |
id | pubmed-7530681 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75306812020-10-19 Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang, Tianyun Hoekzema, Kendra Vecchio, Davide Wu, Huidan Sulovari, Arvis Coe, Bradley P. Gillentine, Madelyn A. Wilfert, Amy B. Perez-Jurado, Luis A. Kvarnung, Malin Sleyp, Yoeri Earl, Rachel K. Rosenfeld, Jill A. Geisheker, Madeleine R. Han, Lin Du, Bing Barnett, Chris Thompson, Elizabeth Shaw, Marie Carroll, Renee Friend, Kathryn Catford, Rachael Palmer, Elizabeth E. Zou, Xiaobing Ou, Jianjun Li, Honghui Guo, Hui Gerdts, Jennifer Avola, Emanuela Calabrese, Giuseppe Elia, Maurizio Greco, Donatella Lindstrand, Anna Nordgren, Ann Anderlid, Britt-Marie Vandeweyer, Geert Van Dijck, Anke Van der Aa, Nathalie McKenna, Brooke Hancarova, Miroslava Bendova, Sarka Havlovicova, Marketa Malerba, Giovanni Bernardina, Bernardo Dalla Muglia, Pierandrea van Haeringen, Arie Hoffer, Mariette J. V. Franke, Barbara Cappuccio, Gerarda Delatycki, Martin Lockhart, Paul J. Manning, Melanie A. Liu, Pengfei Scheffer, Ingrid E. Brunetti-Pierri, Nicola Rommelse, Nanda Amaral, David G. Santen, Gijs W. E. Trabetti, Elisabetta Sedláček, Zdeněk Michaelson, Jacob J. Pierce, Karen Courchesne, Eric Kooy, R. Frank Nordenskjöld, Magnus Romano, Corrado Peeters, Hilde Bernier, Raphael A. Gecz, Jozef Xia, Kun Eichler, Evan E. Nat Commun Article Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort. Nature Publishing Group UK 2020-10-01 /pmc/articles/PMC7530681/ /pubmed/33004838 http://dx.doi.org/10.1038/s41467-020-18723-y Text en © The Author(s) 2020 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Wang, Tianyun Hoekzema, Kendra Vecchio, Davide Wu, Huidan Sulovari, Arvis Coe, Bradley P. Gillentine, Madelyn A. Wilfert, Amy B. Perez-Jurado, Luis A. Kvarnung, Malin Sleyp, Yoeri Earl, Rachel K. Rosenfeld, Jill A. Geisheker, Madeleine R. Han, Lin Du, Bing Barnett, Chris Thompson, Elizabeth Shaw, Marie Carroll, Renee Friend, Kathryn Catford, Rachael Palmer, Elizabeth E. Zou, Xiaobing Ou, Jianjun Li, Honghui Guo, Hui Gerdts, Jennifer Avola, Emanuela Calabrese, Giuseppe Elia, Maurizio Greco, Donatella Lindstrand, Anna Nordgren, Ann Anderlid, Britt-Marie Vandeweyer, Geert Van Dijck, Anke Van der Aa, Nathalie McKenna, Brooke Hancarova, Miroslava Bendova, Sarka Havlovicova, Marketa Malerba, Giovanni Bernardina, Bernardo Dalla Muglia, Pierandrea van Haeringen, Arie Hoffer, Mariette J. V. Franke, Barbara Cappuccio, Gerarda Delatycki, Martin Lockhart, Paul J. Manning, Melanie A. Liu, Pengfei Scheffer, Ingrid E. Brunetti-Pierri, Nicola Rommelse, Nanda Amaral, David G. Santen, Gijs W. E. Trabetti, Elisabetta Sedláček, Zdeněk Michaelson, Jacob J. Pierce, Karen Courchesne, Eric Kooy, R. Frank Nordenskjöld, Magnus Romano, Corrado Peeters, Hilde Bernier, Raphael A. Gecz, Jozef Xia, Kun Eichler, Evan E. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders |
title | Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders |
title_full | Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders |
title_fullStr | Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders |
title_full_unstemmed | Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders |
title_short | Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders |
title_sort | large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530681/ https://www.ncbi.nlm.nih.gov/pubmed/33004838 http://dx.doi.org/10.1038/s41467-020-18723-y |
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