De novo damaging variants associated with congenital heart diseases contribute to the connectome
| Autor: | Dustin Scheinost, Laura R. Ment, Mustafa K. Khokha, Dina J. Ferdman, Weizhen Ji, Joshua A. Copel, Veronika Shabanova, Martina Brueckner |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Heart Defects Congenital Male Heart disease DYRK1A Mutation Missense lcsh:Medicine Nerve Tissue Proteins Protein Tyrosine Phosphatase Non-Receptor Type 11 Gene mutation Bioinformatics Paediatric research Article 03 medical and health sciences 0302 clinical medicine Connectome Genetics Medicine Missense mutation Humans Exome Receptor Notch1 lcsh:Science Homeodomain Proteins Multidisciplinary biology business.industry lcsh:R DNA Helicases Histone-Lysine N-Methyltransferase medicine.disease PTPN11 DNA-Binding Proteins Exact test 030104 developmental biology KMT2A Mutation biology.protein Female lcsh:Q business 030217 neurology & neurosurgery Myeloid-Lymphoid Leukemia Protein Mi-2 Nucleosome Remodeling and Deacetylase Complex |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-11 (2020) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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