## 5 Discussion
There are two main hypotheses with regard to the origin of injury to the brain and subsequent neurodevelopmentalments that arise from the injury: intrinsic patient factors including genetics or altered substrate delivery due to the cardiac malformation. There have been studies looking at the heritability of CHD to determine the genetic causes, which resulted in the finding that CHD most likely has a genetic component. CHD is particularly common in genetic syndromes caused by aneuploidy defects, ranging anywhere from 20-100% of individuals with trisomies 13, 18, and 21 as well as and monosomy X [113], though these syndromic cases account for a relatively low amount of the total CHD population. Additionally, rates of CHD are increased when there are abnormal chromosomal structural syndromes such as deletions, insertions, and copy number variants [114]. Known de novo single-nucleotide polymorphisms account for approximately 10% of CHD cases, roughly the same amount that can be attributed to environmental factors [114; 115]. However, the vast majority of CHD individuals do not have known origin of their cardiac defect nor their neurodevelopmental abnormalities. To overcome this missing data, work has begun looking at previously uncharacterized de novo mutations in mice, singling out genes with human homologs and which have high expression in the heart. When looking at only the homologous genes, researchers found that between CHD and control individuals, there was no significant difference between rates of generic de novo mutations; however, when comparing genes with high cardiac expression, CHD subjects had much higher rates of mutations in protein-altering mutations [116]. This recent work into the genetic origins of CHD has shown that even when the cause of the insult is unknown, the cause of CHD is likely genetic, possibly through the alteration of genes that affect similar downstream pathways. Whether the genetic insult is the main driver or whether the mutations leave the individual susceptible to other forms of injury is unknown. Our group has previously looked at how the developing subcortical paralimbic-related structures of the brain can be linked to energy metabolism and found that subcortical morphological differences were not likely linked to prematurity or white matter injury alone, but that there was a linkage between brain metabolism and subcortical structural morphometry [55]. Stemming from these findings, we believe that subplate vulnerability in the prenatal and immediate post-natal period can be informative to understanding the subcortical dysaturation seen in CHD infants. Within CHD individuals, it has been shown that preoperatively they have volumetric abnormalities present in the cerebellum and brainstem [17] and additionally that abnormal cerebellar growth has been linked with worse outcomes in expressive communication and the adaptive development quotient in CHD individuals [13]. Furthermore, there is an established link between subcortical morphological abnormalities and white matter vulnerability, which can lead to injury and eventual worse neurodevelopmental outcomes [18; 21]. With the mounting evidence of the importance of subcortical structures for proper brain development, and the subcortical structures' relationship to proper cortical development, inclusion of subcortical structures into our scoring system is necessary to characterize the entire picture of brain dysplasia. With nearly half of CHD cases still without a known genetic origin, identifying subtle cases of neurodevelopmental abnormalities in CHD individuals can better help us understand the downstream effects of CHD on brain development, ultimately furthering knowledge of the interplay between CHD and neurodevelopmental outcomes. Importantly, early interventional strategies have shown promise in helping CHD individuals with potential neurocognitive difficulties [117] and early identification of the most vulnerable through proper screening is necessary to identify and target therapies toward highest risk individuals.