The Impact of CNVs on Outcomes for Infants with Single Ventricle Heart Defects

Congenital heart disease (CHD) care has advanced remarkably over the past 40 years.1 This has shifted focus to decreasing morbidity and improving neurologic and developmental outcomes, which are affected by genetic factors. For example, aneuploidies and genomic lesions such as 22q11.2 deletions, are associated with poorer neurocognitive outcomes. For most cases of CHD, however, the underlying genetic basis remains unknown. Identification of causative genetic factors could help to explain a larger percent of the variance in CHD outcomes, and might be useful for patient management as well as clinical trial design. Copy number variants (CNVs), DNA gains or losses greater than 1000 base pairs,2 are detectable due to recent advances in molecular cytogenetics, particularly in microarray-based methods. Using high-resolution, whole-genome scanning methods, it has become evident that a significant proportion of the normal healthy human genome harbors benign CNVs.3, 4 A smaller subset of CNVs, more often large and de novo, are considered pathogenic and are increasingly associated with disease such as schizophrenia and intellectual and developmental disabilities (IDD).5–8 Pathogenic CNV prevalence in CHD has been estimated at 5–15%.9–17 Two small-to-modest-sized studies of patients with hypoplastic left heart syndrome (HLHS), a single ventricle (SV) form of CHD, have suggested that CNV frequency is not increased for that heart lesion.12, 17 CNVs appear to be present at higher rates among patients with CHD plus extracardiac or developmental abnormalities,9–12 although roles for de novo CNVs causing isolated CHD have also been observed.13, 14 No prior study of CNVs has included careful follow-up of outcomes, particularly growth and neurocognitive development, in children with CHD.