Congenital heart disease (CHD) is the most common birth defect affecting approximately 1% of live births. CHD shows a high degree of heritability but the genetic causes are still poorly understood. Many of the known causative genes of CHD are those with roles in gene regulation, such as transcription factors and histone modifiers. One possible explanation of the “missing heritability” of CHD is long non-coding RNAs (lncRNAs), which often act as regulators of gene expression and which have been excluded from previous exome-focussed studies. Previous in vivo and in vitro work has identified six lncRNAs with roles in regulation of heart development (CARMEN, EINCR1, FENDRR, METEOR, STX18-AS1, and UPPERHAND). However, these lncRNAs have not been studied in CHD patients to determine if they have a causal role in CHD. We have used whole genome sequencing data from 607 CHD patients included in the 100,000 Genomes Project to identify variants in these lncRNAs. Variants present in CHD patients in these lncRNAs were filtered against variants in a control set of 68,221 genomes to remove common variants present in the wider population. The control set contains whole genome sequences from gnomAD (genome aggregation database) and individuals from the 100,000 Genomes Project who do not have CHD or related conditions such as syndromes which include CHD (Kabuki syndrome and RASopathies) or other conditions with overlapping aetiologies (aortopathies and neurodevelopmental disorders). Variants in all six tested lncRNAs were significantly enriched (p <0.0001) in CHD patients compared to the control group, with between 8 and 10 times more variants seen per individual, indicating variants in cardiac lncRNAs may contribute to CHD. The identified CHD-unique variants have been cross-referenced with eQTL and predicted secondary structures to prioritise variants which are likely to affect the function of the lncRNA. Where available, parental DNA is used to identify de novo variants in CHD patients with unaffected parents and variants which co-segregate with incidence of CHD in families. In future, prioritised variants will be modelled in suitable in vitro models to measure the effects of the variants on lncRNA function and heart development pathways. This work will allow the contribution of these cardiac lncRNAs to CHD to be studied for the first time.
Conflict of interest None
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.