**6. Complex genetics in HLHS**

Strong evidence of the genetic etiology of HLHS came from the observation that HLHS has a high recurrence risk [45] and is associated with various chromosomal abnormalities [46, 47]. Identifying the genetic causes of HLHS may yield deeper insights into the molecular mechanism driving the pathogenesis of HLHS. In families with HLHS, often bicuspid aortic valve (BAV) is also observed, indicating a genetic link between these two congenital heart lesions [48]. Paradoxically, BAV is the most common CHD (prevalence 1–2%) and is clinically important because of the morbidity and mortality of associated phenotypes, specifically aortic valve disease and aortic aneurysm/dissection (aortopathy). Indeed, BAV underlies aortic valve disease in >50% of patients of all ages undergoing valve surgery [49]. The recurrence of leftsided congenital heart defects in first-degree relatives of a proband of HLHS is about 10–15%, suggestive of a strong but heterogeneous genetic component [45, 47, 50–52]. In addition, there are approximately 30% of fetuses with HLHS that have extracardiac abnormalities [53]. Analysis from the Society of Thoracic Surgeons database from 2002 to 2006 demonstrated mortality after Norwood procedure was significantly worse in HLHS neonates with non-cardiac abnormalities and/or syndromes with higher unfavorable results in patients with chromosomal defects [54].
