Genetics of Congenital Heart Disease

Sponsor

Nationwide Children's Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT01192048

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

1,000

Enrollment

Location

192

Duration (Months)

5.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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, but these genes only account for a minority of the non-syndromic CHDs. Therefore, we are now utilizing whole exome sequencing (WES), 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 WES we are able to sequence all of the genes 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, WES is a robust method for identification of novel genetic causes of CHD which will have important diagnostic and therapeutic consequences for these children.

Condition or Disease	Intervention/Treatment	Phase
Congenital Heart Disease	Other: Blood Sample Collection

Detailed Description

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 (Garg, 2006). 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). 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 (Srivastava and Olson, 2000). Although this approach has been successful (Schluterman, 2007; Rajagopal, 2007; Tomita-Mitchell, 2007; Richards, 2008; Ransom, 2009), it is also limited to the candidate gene lists.

Whole exome sequencing (WES) is a recently developed massively multiplexed sequencing technology that allows for the sequencing of all of the expressed genes. Therefore, this method can be applied to multiplex families and cohorts of sporadic cases to identify genetic causes of CHD in an unbiased manner. WES is dependent on the technical and bioinformatics prowess of the personnel running the WES 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). As other groups have successfully implemented WES into their CHD gene discovery toolkit (Zaidi, 2013; El Turki, 2014)), we expect to do the same. WES is powerful genetic tool that can be used in isolation or in conjunction with other types of genetic analysis (i.e. array comparative genomic hybridization, single nucleotide polymorphisms (SNP) arrays, traditional linkage analysis) to increase the yield of these investigations.

Study Design

Study Type:

Observational

Anticipated Enrollment :

1000 participants

Observational Model:

Family-Based

Time Perspective:

Prospective

Official Title:

Genetics Testing of Individuals and Families With Congenital Heart Disease

Study Start Date :

Dec 1, 2009

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Study Subjects 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 Blood sample collection for direct sequencing, microarray, single nucleotide polymorphism, whole-genome array comparative genomic hybridization DNA analyses, and/or whole exome sequencing.

Arm

Intervention/Treatment

Study Subjects

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

Blood sample collection for direct sequencing, microarray, single nucleotide polymorphism, whole-genome array comparative genomic hybridization DNA analyses, and/or whole exome sequencing.

Outcome Measures

Primary Outcome Measures

Identification of novel genetic contributors to congenital heart defects [up to 3 years, from date of genetic analysis to completion of genetic data analysis or identification of novel genetic contributors, whichever comes first]
Novel genetic abnormalities that are found to be associated with congenital heart defects in humans