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Genetics of Congenital Heart Disease

This study is currently recruiting participants.
Verified February 2017 by Vidu Garg, Nationwide Children's Hospital
ClinicalTrials.gov Identifier:
First Posted: August 31, 2010
Last Update Posted: February 23, 2017
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.
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Vidu Garg, Nationwide Children's Hospital
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. A few genes have been identified by us and other investigators using traditional genetic approaches, but these genes only account for a small portion 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 Intervention
Congenital Heart Disease Other: Blood Sample Collection

Study Type: Observational
Study Design: Observational Model: Family-Based
Time Perspective: Prospective
Official Title: Genetics Testing of Individuals and Families With Congenital Heart Disease

Resource links provided by NLM:

Further study details as provided by Vidu Garg, Nationwide Children's Hospital:

Primary Outcome Measures:
  • 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

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.

Estimated Enrollment: 1000
Study Start Date: December 2009
Estimated Study Completion Date: December 2025
Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
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.

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. At Nationwide Children's Hospital (NCH), our Biomedical Genomics Core 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.


Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
cardiology clinic sample, community sample

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01192048

Contact: Vidu Garg, MD 614-355-5740 vidu.garg@nationwidechildrens.org

United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Principal Investigator: Vidu Garg, MD         
Sponsors and Collaborators
Nationwide Children's Hospital
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Vidu Garg, MD The Research Institute at Nationwide Children's Hospital
  More Information

Pan H, Richards AA, Zhu X, Joglar JA, Yin HL, Garg V. A novel mutation in LAMIN A/C is associated with isolated early-onset atrial fibrillation and progressive atrioventricular block followed by cardiomyopathy and sudden cardiac death. Heart Rhythm. 2009 May;6(5):707-10. doi: 10.1016/j.hrthm.2009.01.037. Epub 2009 Feb 4.
Maitra M, Koenig SN, Srivastava D, Garg V. Identification of GATA6 sequence variants in patients with congenital heart defects. Pediatr Res. 2010 Oct;68(4):281-5. doi: 10.1203/00006450-201011001-00549.
Ransom JF, King IN, Garg V, Srivastava D. A rare human sequence variant reveals myocardin autoinhibition. J Biol Chem. 2008 Dec 19;283(51):35845-52. doi: 10.1074/jbc.M805909200. Epub 2008 Oct 13.
Richards AA, Santos LJ, Nichols HA, Crider BP, Elder FF, Hauser NS, Zinn AR, Garg V. Cryptic chromosomal abnormalities identified in children with congenital heart disease. Pediatr Res. 2008 Oct;64(4):358-63. doi: 10.1203/PDR.0b013e31818095d0.
Schluterman MK, Krysiak AE, Kathiriya IS, Abate N, Chandalia M, Srivastava D, Garg V. Screening and biochemical analysis of GATA4 sequence variations identified in patients with congenital heart disease. Am J Med Genet A. 2007 Apr 15;143A(8):817-23.
Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005 Sep 8;437(7056):270-4. Epub 2005 Jul 17.
Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003 Jul 24;424(6947):443-7. Epub 2003 Jul 6.
Bonachea EM, Chang SW, Zender G, LaHaye S, Fitzgerald-Butt S, McBride KL, Garg V. Rare GATA5 sequence variants identified in individuals with bicuspid aortic valve. Pediatr Res. 2014 Aug;76(2):211-6. doi: 10.1038/pr.2014.67. Epub 2014 May 5.
Bonachea EM, Zender G, White P, Corsmeier D, Newsom D, Fitzgerald-Butt S, Garg V, McBride KL. Use of a targeted, combinatorial next-generation sequencing approach for the study of bicuspid aortic valve. BMC Med Genomics. 2014 Sep 26;7:56. doi: 10.1186/1755-8794-7-56.
LaHaye S, Corsmeier D, Basu M, Bowman JL, Fitzgerald-Butt S, Zender G, Bosse K, McBride KL, White P, Garg V. Utilization of Whole Exome Sequencing to Identify Causative Mutations in Familial Congenital Heart Disease. Circ Cardiovasc Genet. 2016 Aug;9(4):320-9. doi: 10.1161/CIRCGENETICS.115.001324. Epub 2016 Jul 14.
Hanchard NA, Swaminathan S, Bucasas K, Furthner D, Fernbach S, Azamian MS, Wang X, Lewin M, Towbin JA, D'Alessandro LC, Morris SA, Dreyer W, Denfield S, Ayres NA, Franklin WJ, Justino H, Lantin-Hermoso MR, Ocampo EC, Santos AB, Parekh D, Moodie D, Jeewa A, Lawrence E, Allen HD, Penny DJ, Fraser CD, Lupski JR, Popoola M, Wadhwa L, Brook JD, Bu'Lock FA, Bhattacharya S, Lalani SR, Zender GA, Fitzgerald-Butt SM, Bowman J, Corsmeier D, White P, Lecerf K, Zapata G, Hernandez P, Goodship JA, Garg V, Keavney BD, Leal SM, Cordell HJ, Belmont JW, McBride KL. A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20. Hum Mol Genet. 2016 Jun 1;25(11):2331-2341. Epub 2016 Mar 9.
Garg V. Insights into the genetic basis of congenital heart disease. Cell Mol Life Sci. 2006 May;63(10):1141-8. Review.
Srivastava D, Olson EN. A genetic blueprint for cardiac development. Nature. 2000 Sep 14;407(6801):221-6. Review.

Responsible Party: Vidu Garg, Investigator and Associate Professor, Nationwide Children's Hospital
ClinicalTrials.gov Identifier: NCT01192048     History of Changes
Other Study ID Numbers: IRB09-00339
R01HL109758-03 ( U.S. NIH Grant/Contract )
First Submitted: August 30, 2010
First Posted: August 31, 2010
Last Update Posted: February 23, 2017
Last Verified: February 2017

Keywords provided by Vidu Garg, Nationwide Children's Hospital:
Congenital Heart Disease
birth defect
direct sequencing
single nucleotide polymorphism
whole genome array comparative genomic hybridization
chromosomal copy number change
nucleotide sequence variation
exome sequencing
whole exome sequencing

Additional relevant MeSH terms:
Heart Diseases
Heart Defects, Congenital
Cardiovascular Diseases
Cardiovascular Abnormalities
Congenital Abnormalities

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