Genetics of Congenital Heart Disease - Full Text View

Purpose

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. The investigators are researching the potential genetic causes of congenital heart disease and have taken two approaches to uncover these genetic contributors. The first requires the identification of multi-generation families with several affected members. Traditional genetic approaches can be used to analyze these families, investigators have successfully discovered several genetic causes of human CHD in this manner. This approach to identify novel genetic etiologies is limited by the scarcity of suitable pedigrees and to mild forms of congenital heart disease since severe heart defects are often lethal in childhood. The investigators are also utilizing a second approach to identify novel genetic etiologies of congenital heart disease. This approach will involve the identification of families with either isolated CHD or those with only two or three affected members. In brief, DNA (deoxyribonucleic acid) will be extracted from blood collected from individuals with CHD and/or their family members. The DNA will be analyzed by direct sequencing and/or microarray for point mutations or single nucleotide polymorphisms in known cardiac development genes or novel candidate genes for CHD. In addition, the DNA may be analyzed for small pieces of extra or missing chromosomal DNA using a relatively new technology, whole-genome array comparative genomic hybridization (CGH). The investigators hypothesize that children with CHD have genetic abnormalities that are not detected by currently available genetic testing. This research will allow investigators to determine the frequency of subtle or cryptic genetic abnormalities in children with CHD. Identification of novel genetic causes of CHD 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:

MedlinePlus related topics: Heart Diseases

U.S. FDA Resources

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

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 2014
Estimated Primary Completion Date:	December 2014 (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	Other: Blood Sample Collection Blood sample collection for direct sequencing, microarray, single nucleotide polymorphism, and/or whole-genome array comparative genomic hybridization DNA analyses

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. In addition, most of these discoveries have been limited to milder forms of CHD that have allowed for the generation of large kindreds.

The other modality involves the screening of large populations of children with sporadic (non-familial) cases of CHD for genetic abnormalities (nucleotide sequence variations or chromosomal copy number changes) in candidate genes for CHD. Studies using numerous species has led to the elucidation of the molecular pathways critical for normal cardiac development and also contributed to the identification of numerous genes necessary for this complex morphogenetic process. These discoveries have resulted in the generation of large number of candidate genes that may be responsible for CHD in humans (Srivastava and Olson, 2000). This approach has been successful in the identification of etiologic genes for CHD and when performed in a coordinated and careful manner will lead to significant advances in our understanding of the genetic contributors to CHD (Garg, 2006). In support of this approach, my laboratory has successfully used these screening approaches to identify novel genetic abnormalities in children with CHD (Schluterman, 2007; Richards, 2008; Ransom, 2009; Maitra, 2010).

Eligibility


Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes
Sampling Method:	Non-Probability Sample

Study Population

cardiology clinic sample, community sample

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01192048

Contacts


Contact: Vidu Garg, MD	614-355-3091	vidu.garg@nationwidechildrens.org

Locations


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

Investigators


Principal Investigator:	Vidu Garg, MD	The Research Institute at Nationwide Children's Hospital

More Information

Publications:

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.

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
Study First Received:	August 30, 2010
Last Updated:	February 21, 2012
Health Authority:	United States: Institutional Review Board United States: Food and Drug Administration

Keywords provided by Nationwide Children's Hospital:


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

Additional relevant MeSH terms:


Heart Defects, Congenital Heart Diseases Cardiovascular Abnormalities Cardiovascular Diseases Congenital Abnormalities

ClinicalTrials.gov processed this record on February 27, 2015