Congenital Heart Disease and Neurodevelopment: Clinical Manifestations, Genetics, Mechanisms, and Implications  Sarah N. Nattel, BA, Laura Adrianzen, MD, Erica C. Kessler, RN, Gregor Andelfinger, MD, Mathieu Dehaes, PhD, Gabriel Côté- Corriveau, MD, M. Pilar Trelles, MD  Canadian Journal of Cardiology  Volume 33, Issue 12, Pages 1543-1555 (December 2017) DOI: 10.1016/j.cjca.2017.09.020 Copyright © 2017 Canadian Cardiovascular Society Terms and Conditions

Figure 1 A summary of the neurodevelopmental deficits observed in children who underwent corrective surgery for congenital heart disease. Aspects of neurodevelopment can be divided into 4 groups. Solid line, executive function, a broad term encompassing cognitive skills that are required for regulation of behaviour and goal-directed activity. (Brown dashed line) Cognition and adaptive function. Adaptive function refers to the ability to use cognition to learn and apply skills necessary for everyday life. (Green dotted line) Speech/language and motor function both involve motor ability as well as coordination and planning. (Blue dotted line) Neuropsychiatric category, including deficits related to autism spectrum disorder, and behavioural/psychiatric conditions. ADHD, attention deficit hyperactivity disorder; ADLs, activities of daily living. Canadian Journal of Cardiology 2017 33, 1543-1555DOI: (10.1016/j.cjca.2017.09.020) Copyright © 2017 Canadian Cardiovascular Society Terms and Conditions

Figure 2 Schematic diagram illustrating key cellular functions believed to be associated with important gene variants implicated in congenital heart disease associated with neurodevelopmental disorders. The affected genes or gene families are shown in black font, associated cell functions are encircled by dashed lines. The affected cell functions are all related to developmental regulation: gap junctions mediate cell-to-cell communication, signal transduction and transcription regulation control govern gene expression, and cell stability is involved in resistance to cell death. Canadian Journal of Cardiology 2017 33, 1543-1555DOI: (10.1016/j.cjca.2017.09.020) Copyright © 2017 Canadian Cardiovascular Society Terms and Conditions

Figure 3 The pathophysiology of neurodevelopmental deficits seen in patients with congenital heart disease (CHD). This can be looked at from different perspectives, all of which are likely to be contributory to the observed phenotype. Abnormalities in genes affecting both heart and brain development (top circle) point to a common underlying genetic cause of both the cardiac and neurodevelopmental deficits, in which the deficits are correlated with each other but are not causal. Alterations in cerebral circulation and metabolism both in utero and perioperatively (bottom right circle) have been proposed based on magnetic resonance imaging studies showing unique patterns of change in the brains of patients with CHD. Patterns of white matter injury correspond to anatomic maps of specific cell types seen in particular phases of development, which are likely affected by changes in cerebral blood flow in CHD at key developmental moments. Potentially modifiable factors during the vulnerable period between birth and surgery (bottom left circle) also play an important role. Preterm infants with CHD have poorer neurodevelopmental outcomes, as do infants with longer time from birth to corrective surgery— in both cases, the vulnerable infant brain is subject to suboptimal conditions at a critical stage of neurodevelopment. Canadian Journal of Cardiology 2017 33, 1543-1555DOI: (10.1016/j.cjca.2017.09.020) Copyright © 2017 Canadian Cardiovascular Society Terms and Conditions