Genetic burden and associations with adverse neurodevelopment in neonates with congenital heart disease - 18/06/18
Abstract |
Background |
Up to 20% of children with congenital heart disease (CHD) undergoing cardiac surgery develop neurodevelopmental disabilities (NDD), with some studies reporting persistent impairment. Recent large-scale studies have demonstrated shared genetic mechanisms contributing to CHD and NDD. In this study, a targeted approach was applied to assess direct clinical applicability of this information.
Methods |
A gene panel comprising 148 known CHD and/or NDD genes was used to sequence 15 patients with CHD + NDD, 15 patients with CHD, and 15 healthy controls. The number and types of variants between the 3 groups were compared using Poisson log-linear regression, and the SNP-set (Sequence) Kernel Association Test-Optimized was used to conduct single-gene and gene-pathway burden analyses.
Results |
A significant increase in rare (minor allele frequency < 0.01) and novel variants was identified between the CHD + NDD cohort and controls, P < .001 and P = .001, respectively. There was also a significant increase in rare variants in the CHD cohort compared with controls (P = .04). Rare variant burden analyses implicated pathways associated with “neurotransmitters,” “axon guidance,” and those incorporating “RASopathy” genes in the development of NDD in CHD patients.
Conclusions |
These findings suggest that an increase in novel and rare variants in known CHD and/or NDD genes is associated with the development of NDD in patients with CHD. Furthermore, burden analyses point toward rare variant burden specifically in pathways related to brain development and function as contributors to NDD. Although promising variants and pathways were identified, further research, utilizing whole-genome approaches, is required prior to demonstrating clinical utility in this patient group.
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| Disclosures: None. All authors have approved the final article. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents. |
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| Conflicts of interest: None. |
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| Key messages: What is already known on this subject? Up to 20% of children undergoing neonatal cardiac surgery develop neurodevelopmental disabilities (NDD). Recent studies have confirmed a previously suggested genetic link between heart and brain development. The relevance of these findings in a clinical setting has not yet been established. What might this study add? This is the first study to assess the clinical applicability of these recent findings for patients with congenital heart disease (CHD) ± NDD using a targeted gene panel-based approach. This identified a number of promising genetic variants and pathways associated with the development of NDD in patients with CHD. Furthermore, the findings point toward rare variant burden specifically in pathways related to brain development and function as contributors toward NDD. How might this impact on clinical practice? This study highlights the contribution of genetic burden, specifically the burden of novel and rare variants in known CHD and/or NDD genes in the development of both NDD and CHD. Although promising variants and pathways were identified, analysis of larger cohorts of neonates with sporadic CHD ± NDD is required, probably using whole-genome sequencing. Variant burden and more subtle genetic changes are likely to be the basis of comparative evaluation unlike identification of causal variants in structural heart disease which can be effectively achieved using a targeted gene panel. |
Vol 201
P. 33-39 - juillet 2018 Retour au numéro
Article précédent
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