Insights into the genetic architecture underlying complex, critical congenital heart disease.
Presented By:
Gillian M. Blue, Eddie K. K. Ip, Michael Troup, Russell C. Dale, Gary F. Sholler, Richard P. Harvey, Sally L. Dunwoodie, Eleni Giannoulatou, David S. Winlaw
Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia
gillian.blue@health.nsw.gov.auOverview:
Background: Congenital heart disease (CHD) has a multifactorial aetiology, raising the possibility of an underlying genetic burden, predisposing to disease but also variable expression, including variation in disease severity, and incomplete penetrance. Understanding the heritable component contributing to reduced penetrance and variable expression to prevent/ameliorate disease severity in future generations, is important and relevant to the aging CHD population. Using whole genome sequencing, the genetic composition underlying CHD severity and complexity was investigated.
Methods: Patients with severe CHD (complex CHD requiring neonatal surgery, n=23), were compared to patients with CHD requiring surgical intervention after the neonatal period (n=39). Initial genome analyses utilised a high-confidence CHD (hcCHD) gene list comprising 107 established CHD genes. Subsequent analyses extended to the exome. Poisson regression was used to compare genetic variants between patient groups and Fisher’s exact test to assess variant burden.
Results: Analyses of hcCHD genes in the cohort, identified significantly more common variants in severe cases (p=0.011). Conversely, severe CHD cases had significantly fewer low-frequency variants (p=0.02) and fewer rare variants (p=0.06) in established CHD genes. Extending the analysis to the exome, identified significantly less rare (p<0.001) and low-frequency variants (p<0.001) in severe CHD cases. There were significantly fewer novel variants among severe CHD cases across the exome (p=0.009). Gene-based variant burden identified significant associations between common variants in KAT6A and disease severity, and rare and low-frequency variant burden, implicated pathways associated with ‘Autoimmune thyroid disease’ and ‘Type 1 diabetes mellitus’.
Conclusions: These preliminary findings suggest that the genetic architecture of complex, critical CHD is distinct from other types of CHD due to a significant increase in common variation, specifically among hcCHD genes. Further, these findings highlight associations with regulatory genes and environmental ‘stressors’ (modifiable factors affecting the fetal-placental-maternal environment) involved in the final presentation of disease. Validation in larger cohorts, may clarify the contribution of modifying variants and their effects on variable expression, specifically relating to disease severity.
Methods: Patients with severe CHD (complex CHD requiring neonatal surgery, n=23), were compared to patients with CHD requiring surgical intervention after the neonatal period (n=39). Initial genome analyses utilised a high-confidence CHD (hcCHD) gene list comprising 107 established CHD genes. Subsequent analyses extended to the exome. Poisson regression was used to compare genetic variants between patient groups and Fisher’s exact test to assess variant burden.
Results: Analyses of hcCHD genes in the cohort, identified significantly more common variants in severe cases (p=0.011). Conversely, severe CHD cases had significantly fewer low-frequency variants (p=0.02) and fewer rare variants (p=0.06) in established CHD genes. Extending the analysis to the exome, identified significantly less rare (p<0.001) and low-frequency variants (p<0.001) in severe CHD cases. There were significantly fewer novel variants among severe CHD cases across the exome (p=0.009). Gene-based variant burden identified significant associations between common variants in KAT6A and disease severity, and rare and low-frequency variant burden, implicated pathways associated with ‘Autoimmune thyroid disease’ and ‘Type 1 diabetes mellitus’.
Conclusions: These preliminary findings suggest that the genetic architecture of complex, critical CHD is distinct from other types of CHD due to a significant increase in common variation, specifically among hcCHD genes. Further, these findings highlight associations with regulatory genes and environmental ‘stressors’ (modifiable factors affecting the fetal-placental-maternal environment) involved in the final presentation of disease. Validation in larger cohorts, may clarify the contribution of modifying variants and their effects on variable expression, specifically relating to disease severity.
