Genetic Testing of Individuals and Families with Congenital Heart Disease

Congenital heart disease (CHD) is the most common type of birth defect, but the etiology of CHD remains largely unknown. Genetic causes have been discovered for both syndromic and non-syndromic CHD utilizing several genetic approaches (Yasuhara and Garg, 2021). The majority of these genetic causes have found by studying large families with autosomal dominant congenital heart disease and my laboratory has successfully used this methodology in the past (Garg, 2003; Garg 2005; Pan, 2009; Bennett, 2022). Although these positional cloning approaches are very powerful, they are limited by rare nature of multi-generation pedigrees and are limited to milder forms of CHD that have allowed for the generation of large kindreds.

The other method that has traditionally been utilized to identify genetic causes of CHD is the screening of large populations of children with sporadic (non-familial) cases of CHD for genetic abnormalities (nucleotide sequence variations in candidate genes for CHD or for chromosomal copy number changes that involve CHD-candidate genes). This work has been tedious as a large number of candidate genes have been implicated as potentially responsible for CHD in humans (Choudhury and Garg, 2022). Although this approach has been successful (Schluterman, 2007; Maitra, 2010; Chang, 2013; Bonachea, 2014), it is also limited to the candidate gene lists.

Whole exome sequencing (WES) is a next-generation sequencing technology that allows for the sequencing of all of the expressed genes. Our group, in addition to several others (LaHaye, 2016; Gordon, 2022), has been utilizing WES technology for CHD gene discovery. Our group has progressed to utilizing whole genome sequencing (WGS), a next-generation sequencing technology that allows for the sequencing of all genetic material (including genomic regions that are not sequenced in WES), in our analysis for CHD gene discovery. Therefore, these sequencing methods can be applied to multiplex families and cohorts of sporadic cases to identify genetic causes of CHD in an unbiased manner. Genomic sequencing is dependent on the technical and bioinformatics prowess of the personnel running the sequencing and the controlling the data pipeline. The Institute of Genomic Medicine at Nationwide Children's Hospital (NCH) is both technically skilled and have developed their own powerful data pipeline (Kelly, 2015). WGS is a powerful genetic tool that can be used in isolation or in conjunction with other types of genetic analysis to increase the yield of these investigations.