Cargando…
De novo damaging variants associated with congenital heart diseases contribute to the connectome
Congenital heart disease (CHD) survivors are at risk for neurodevelopmental disability (NDD), and recent studies identify genes associated with both disorders, suggesting that NDD in CHD survivors may be of genetic origin. Genes contributing to neurogenesis, dendritic development and synaptogenesis...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184603/ https://www.ncbi.nlm.nih.gov/pubmed/32341405 http://dx.doi.org/10.1038/s41598-020-63928-2 |
_version_ | 1783526618173538304 |
---|---|
author | Ji, Weizhen Ferdman, Dina Copel, Joshua Scheinost, Dustin Shabanova, Veronika Brueckner, Martina Khokha, Mustafa K. Ment, Laura R. |
author_facet | Ji, Weizhen Ferdman, Dina Copel, Joshua Scheinost, Dustin Shabanova, Veronika Brueckner, Martina Khokha, Mustafa K. Ment, Laura R. |
author_sort | Ji, Weizhen |
collection | PubMed |
description | Congenital heart disease (CHD) survivors are at risk for neurodevelopmental disability (NDD), and recent studies identify genes associated with both disorders, suggesting that NDD in CHD survivors may be of genetic origin. Genes contributing to neurogenesis, dendritic development and synaptogenesis organize neural elements into networks known as the connectome. We hypothesized that NDD in CHD may be attributable to genes altering both neural connectivity and cardiac patterning. To assess the contribution of de novo variants (DNVs) in connectome genes, we annotated 229 published NDD genes for connectome status and analyzed data from 3,684 CHD subjects and 1,789 controls for connectome gene mutations. CHD cases had more protein truncating and deleterious missense DNVs among connectome genes compared to controls (OR = 5.08, 95%CI:2.81–9.20, Fisher’s exact test P = 6.30E-11). When removing three known syndromic CHD genes, the findings remained significant (OR = 3.69, 95%CI:2.02–6.73, Fisher’s exact test P = 1.06E-06). In CHD subjects, the top 12 NDD genes with damaging DNVs that met statistical significance after Bonferroni correction (PTPN11, CHD7, CHD4, KMT2A, NOTCH1, ADNP, SMAD2, KDM5B, NSD2, FOXP1, MED13L, DYRK1A; one-tailed binomial test P ≤ 4.08E-05) contributed to the connectome. These data suggest that NDD in CHD patients may be attributable to genes that alter both cardiac patterning and the connectome. |
format | Online Article Text |
id | pubmed-7184603 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-71846032020-04-29 De novo damaging variants associated with congenital heart diseases contribute to the connectome Ji, Weizhen Ferdman, Dina Copel, Joshua Scheinost, Dustin Shabanova, Veronika Brueckner, Martina Khokha, Mustafa K. Ment, Laura R. Sci Rep Article Congenital heart disease (CHD) survivors are at risk for neurodevelopmental disability (NDD), and recent studies identify genes associated with both disorders, suggesting that NDD in CHD survivors may be of genetic origin. Genes contributing to neurogenesis, dendritic development and synaptogenesis organize neural elements into networks known as the connectome. We hypothesized that NDD in CHD may be attributable to genes altering both neural connectivity and cardiac patterning. To assess the contribution of de novo variants (DNVs) in connectome genes, we annotated 229 published NDD genes for connectome status and analyzed data from 3,684 CHD subjects and 1,789 controls for connectome gene mutations. CHD cases had more protein truncating and deleterious missense DNVs among connectome genes compared to controls (OR = 5.08, 95%CI:2.81–9.20, Fisher’s exact test P = 6.30E-11). When removing three known syndromic CHD genes, the findings remained significant (OR = 3.69, 95%CI:2.02–6.73, Fisher’s exact test P = 1.06E-06). In CHD subjects, the top 12 NDD genes with damaging DNVs that met statistical significance after Bonferroni correction (PTPN11, CHD7, CHD4, KMT2A, NOTCH1, ADNP, SMAD2, KDM5B, NSD2, FOXP1, MED13L, DYRK1A; one-tailed binomial test P ≤ 4.08E-05) contributed to the connectome. These data suggest that NDD in CHD patients may be attributable to genes that alter both cardiac patterning and the connectome. Nature Publishing Group UK 2020-04-27 /pmc/articles/PMC7184603/ /pubmed/32341405 http://dx.doi.org/10.1038/s41598-020-63928-2 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 Ji, Weizhen Ferdman, Dina Copel, Joshua Scheinost, Dustin Shabanova, Veronika Brueckner, Martina Khokha, Mustafa K. Ment, Laura R. De novo damaging variants associated with congenital heart diseases contribute to the connectome |
title | De novo damaging variants associated with congenital heart diseases contribute to the connectome |
title_full | De novo damaging variants associated with congenital heart diseases contribute to the connectome |
title_fullStr | De novo damaging variants associated with congenital heart diseases contribute to the connectome |
title_full_unstemmed | De novo damaging variants associated with congenital heart diseases contribute to the connectome |
title_short | De novo damaging variants associated with congenital heart diseases contribute to the connectome |
title_sort | de novo damaging variants associated with congenital heart diseases contribute to the connectome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184603/ https://www.ncbi.nlm.nih.gov/pubmed/32341405 http://dx.doi.org/10.1038/s41598-020-63928-2 |
work_keys_str_mv | AT jiweizhen denovodamagingvariantsassociatedwithcongenitalheartdiseasescontributetotheconnectome AT ferdmandina denovodamagingvariantsassociatedwithcongenitalheartdiseasescontributetotheconnectome AT copeljoshua denovodamagingvariantsassociatedwithcongenitalheartdiseasescontributetotheconnectome AT scheinostdustin denovodamagingvariantsassociatedwithcongenitalheartdiseasescontributetotheconnectome AT shabanovaveronika denovodamagingvariantsassociatedwithcongenitalheartdiseasescontributetotheconnectome AT bruecknermartina denovodamagingvariantsassociatedwithcongenitalheartdiseasescontributetotheconnectome AT khokhamustafak denovodamagingvariantsassociatedwithcongenitalheartdiseasescontributetotheconnectome AT mentlaurar denovodamagingvariantsassociatedwithcongenitalheartdiseasescontributetotheconnectome |