CHDgene: A Curated Database for Congenital Heart Disease Genes

Congenital heart disease (CHD) defines any malformation of the cardiovascular system present at birth with an incidence of 1% of live births.¹ Although several recent studies have performed exome or genome sequencing to identify the genetic causes of CHD, a comprehensive resource of genes linked to CHD causation is not currently available. Studies often use candidate gene lists but do not provide sufficient information, such as original citations, on how these are generated. Additionally, studies frequently use gene lists that are not curated but automatically extracted by gene disease databases such as ClinVar or OMIM. Automated gene list generation might miss genes associated with CHD or include genes not supported by enough evidence. As a result, this hinders the identification of clinically reportable or actionable variants in affected patients.

We have developed CHDgene (http://chdgene.victorchang.edu.au/): a curated database that contains essential information about the genes that have been reproducibly shown to cause CHD when mutated in humans. An initial version of our database has been used by the first genome-sequencing study of patients with CHD that identified a reportable variant in 31% of families.² Given that the majority of patients with CHD do not currently receive a genetic diagnosis, many more genes are expected to be involved in CHD causation, with a recent estimate of ≈440 genes inferred to contribute to sporadic CHD.³ The search for genetic causes of CHD requires a constantly up-to-date resource on the genetics of CHD. CHDgene provides this, and as our multidisciplinary team continues to investigate the genetics of CHD, we commit to keeping this information up-to-date.

The criteria for inclusion of a gene in our database as a CHD gene are strict to ensure that variants in these genes are clinically actionable.⁴ Genes are only included in the database if variants in the respective gene have been reported as the monogenic cause for CHD (isolated or in the context of a syndrome) in at least 3 independent familial or sporadic cases in one or more separate publications.

CHDgene provides useful information about the genes linked to CHD causation: classification of cardiac malformations, whether variants can cause extracardiac phenotypes, modes of inheritance of variants in the genes, presence of incomplete penetrance or variable expressivity, the corresponding pathogenic and likely pathogenic variants as reported on ClinVar and information on animal models (Figure).

CHDgene was developed in Python 3 using Flask web framework and MySQL 5.7 database engine. The server-side application was implemented in Python using python packages including SQLAlchemy and mysqlclient for interacting with the database engine. The web interface was developed with Bootstrap. The gene list table was implemented using the tablesorter jQuery plug-in. Finally, igv.js library was used to embed the Integrative Genomics Viewer genome browser for visualizing variants from ClinVar.

CHDgene provides comprehensive information that can be used for the identification of clinically reportable variants according to the guidelines of the American College of Medical Genetics and Genomics⁵ and thereby facilitates genetic diagnosis of CHD. At the same time, CHDgene can serve as a useful resource for any cardiovascular disease researcher as it provides valuable information on disease genes and their associated phenotypes.