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Genetics of Congenital Heart Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01192048
Recruitment Status : Recruiting
First Posted : August 31, 2010
Last Update Posted : August 18, 2020
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Vidu Garg, Nationwide Children's Hospital

Tracking Information
First Submitted Date August 30, 2010
First Posted Date August 31, 2010
Last Update Posted Date August 18, 2020
Study Start Date December 2009
Estimated Primary Completion Date December 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: June 29, 2015)
Identification of novel genetic contributors to congenital heart defects [ Time Frame: 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
Original Primary Outcome Measures Not Provided
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title Genetics of Congenital Heart Disease
Official Title Genetics Testing of Individuals and Families With Congenital Heart Disease
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.
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 Type Observational
Study Design Observational Model: Family-Based
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Blood samples will be collected in vacuum tubes containing acid citrate dextrose (ACD). Lymphocytes from blood drawn in appropriate anticoagulant (ACD) may be stored for subsequent immortalization. DNA will be extracted from these samples for analysis.
Sampling Method Non-Probability Sample
Study Population cardiology clinic sample, community sample
Condition Congenital Heart Disease
Intervention 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.
Study Groups/Cohorts 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.
Intervention: Other: Blood Sample Collection
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: August 30, 2010)
Original Estimated Enrollment Same as current
Estimated Study Completion Date December 2025
Estimated Primary Completion Date December 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria

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: All
Ages Child, Adult, Older Adult
Accepts Healthy Volunteers Yes
Contact: Katherine J Myers, MS, CGC 614-355-6388
Listed Location Countries United States
Removed Location Countries  
Administrative Information
NCT Number NCT01192048
Other Study ID Numbers IRB09-00339
R01HL109758-03 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Vidu Garg, Nationwide Children's Hospital
Study Sponsor Nationwide Children's Hospital
Collaborators National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Vidu Garg, MD The Research Institute at Nationwide Children's Hospital
PRS Account Nationwide Children's Hospital
Verification Date August 2020