De novo damaging variants associated with congenital heart diseases contribute to the connectome


Ji W, Ferdman D, Copel J, Scheinost D, Shabanova V, Brueckner M, Khokha MK, Ment LR.

Sci Rep. 2020 Apr 27;10(1):7046. doi: 10.1038/s41598-020-63928-2.

PMID: 32341405 Free PMC Article

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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.


Figure 1 Characterization of the 229 Neurodevelopmental Disorder (NDD) genes. Review of the literature demonstrated that 129 of the published 229 NDD genes contributed to the connectome, 13 were chromatin modifiers, and 30 were chromatin modifiers that contributed to the connectome. Fifty-seven were neither chromatin modifiers nor connectome genes.


Figure 2 Functions of the top 12 over-represented genes with damaging DNVs. Review of the published literature for the identified top 12 enriched genes achieving statistical significance after correction for multiple comparisons revealed that 11 contributed to neurogenesis and one, CHD4, contributed to dendritic plasticity and synaptogenesis. Of the 11 contributing to neurogenesis, four genes, ADNP, DYRKIA, NOTCH1 and PTPN11, also contributed to dendritic plasticity and synaptogenesis. One, SMAD2, also subserved dendritic plasticity, and a single gene, KMT2A contributed to both neurogenesis and synaptogenesis. Five of the top genes were chromatin modifiers.