Genetics of Congenital Heart Disease

Study Overview
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Brief Summary
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Congenital heart disease (CHD) is the most common type of birth defect but the cause for the majority of cardiac birth defects remains unknown. Numerous epidemiologic studies have demonstrated evidence that genetic factors likely play a contributory, if not causative, role in CHD. While numerous genes have been identified by us and other investigators using traditional genetic approaches, these genes only account for a minority of the non-syndromic CHDs. Therefore, we are now utilizing whole genome sequencing (WGS), with the addition of more traditional genetic techniques such as chromosomal microarray or traditional linkage analysis, to identify genetic causes of familial and isolated CHD. With WGS we are able to sequence all of the genetic material of an individual and apply different data analysis techniques based on whether we are analyzing a multiplex family or a cohort of trios (mother, father and child with CHD) with a specific isolated CHD. Therefore, WGS is a robust method for identification of novel genetic causes of CHD which will have important diagnostic and therapeutic consequences for these children.

Detailed Description
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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.

Official Title
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Genetics Testing of Individuals and Families With Congenital Heart Disease

Conditions
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Congenital Heart Disease

Intervention / Treatment
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* Other: Blood Sample Collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have a diagnosis of Congenital Heart Disease or be related to individuals with Congenital Heart Disease. Exclusion Criteria: Healthy individuals unrelated to those with Congenital Heart Disease
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Study Subjects<br>Individuals with Congenital Heart Disease and family members with or without Congenital Heart Disease. A blood sample collection will be required for all study participants. | Other: Blood Sample Collection<br>* Blood sample collection for direct sequencing, microarray, single nucleotide polymorphism, whole-genome array comparative genomic hybridization DNA analyses, and/or whole exome or genome sequencing.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification of novel genetic contributors to congenital heart defects | Novel genetic abnormalities that are found to be associated with congenital heart defects in humans | up to 3 years, from date of genetic analysis to completion of genetic data analysis or identification of novel genetic contributors, whichever comes first | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Congenital Heart Disease, birth defect, genetics, gene, DNA, direct sequencing, microarray, single nucleotide polymorphism, whole genome array comparative genomic hybridization, chromosomal copy number change, nucleotide sequence variation, exome sequencing, whole exome sequencing, whole genome sequencing