**6.4 The complex genetics driving the cardiac and neurodevelopmental outcomes in HLHS patients**

Many studies have shown patients with complex CHD, especially those with HLHS, have impaired neurodevelopment associated with developmental delay, learning disabilities, behavioral deficits, and cognitive impairment [92–97]. The etiology of the cognitive impairment in HLHS had been generally assumed to arise from hypoxic injury (prior to palliation) and/or complications from medical/surgical management. Clinical studies analyzing various risk elements (cardiopulmonary bypass time, hypothermia, etc) in the Single Ventricle Reconstruction Trial showed such factors can explain some of variance in HLHS outcomes which suggests patient intrinsic factors may contribute to the cause of the poor neurodevelopmental outcomes in SV-CHD patients [92]. A shared genetic etiology for CHD and brain abnormalities has been indicated by a large-scale human genomic study [98] as well as studies of HLHS mutant mouse models. Mouse models of HLHS were also observed to exhibit brain

abnormalities, suggesting that mutations causing the cardiac lesion in HLHS can also cause brain defects that could contribute to the poor neurodevelopmental outcome in HLHS patients [99–101]. The brain phenotypes observed in the HLHS mice included microcephaly, which has also been reported in HLHS patients [99, 101]. Also seen were other brain abnormalities largely confined to forebrain structures, including the cerebral cortex, hippocampus, corpus callosum, cerebellum, and olfactory bulbs. In contrast, the midbrain and hindbrain structures were mostly spared. These findings suggest abnormal brain development with regional brain dysplasia may drive the neurodevelopmental delay and neurocognitive impairment associated with HLHS.
