1. Introduction

Neurodevelopmental disorders (NDD) are common comorbidities amongst patients with congenital heart disease (CHD), with an estimated prevalence of 35% of CHD patients reported to have some form of NDD, compared with 3%–11% in the general population [1, 2]. NDD includes a spectrum of conditions that alter cognitive, motor, emotional and behavioural development and may cause an increased risk of educational and behavioural problems. There are several known risk factors that contribute to the co‐occurrence of these conditions, including the severity of cardiovascular anomalies, need for neonatal cardiac surgery and prolonged hospitalisation and family socioeconomic disadvantage [3]. In utero, fetuses with severe CHD may experience reduced cerebral oxygenation and nutrient delivery due to abnormal cardiac physiology. These prenatal alterations in cerebral perfusion have been associated with impaired brain growth, including reductions in total and regional brain volumes [4]. Perioperative exposures in the neonatal period may impose additional physiological stress on the developing brain, further increasing vulnerability [5]. These established risk factors link CHD and NDD; yet, when combined, only explain up to 45% of the variability in neurodevelopmental outcomes. Therefore, it is hypothesised that other risk factors, such as genetics, may play a role.

Several recent studies have begun to investigate the genetic overlap between CHD and NDD and have uncovered variants in genes critical for early cardiac and neural development [6–9]. For example, CHD patients have an increased number of protein‐truncating and deleterious missense de novo variants in genes involved in neurogenesis, dendritic development and synaptogenesis [6]. Patients with CHD and NDD may also have greater numbers of protein‐damaging de novo mutations in genes highly expressed in the developing heart and brain compared with patients with isolated CHD [9]. Identification of these variants suggests there may be many developmental genes with a pleiotropic effect, contributing to the high prevalence of NDD within CHD patients; however, our understanding of the molecular pathways linking these disorders remains incomplete.

The aim of this study was to investigate shared molecular pathways between CHD and NDD by identifying genetic variants in developmentally relevant genes in probands with NDD and/or CHD. In addition, this study is aimed at using RNA sequencing and DNA methylation data to provide an overview of the gene expression and methylation changes associated with NDD and CHD.