Genetics of Congenital Heart Disease

• ClinicalTrials.gov Identifier: NCT01192048
• Recruitment Status: Recruiting
• First Posted: August 31, 2010
• Last Update Posted: August 24, 2021
• Sponsor: Nationwide Children's Hospital
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Vidu Garg, Nationwide Children's Hospital

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
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
• Estimated 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: December 2009
• Estimated Primary Completion Date: December 2025
• Estimated Study Completion Date: December 2025

Groups and Cohorts

Group/Cohort	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 :

1. 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.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• 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

Contacts

Contact: Katherine J Myers, MS, CGC; 614-355-6388; katherine.myers@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

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

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

More Information

Publications of Results:

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.

Other Publications:

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, Director and Professor, Nationwide Children's Hospital
• ClinicalTrials.gov Identifier: NCT01192048
• Other Study ID Numbers: IRB09-00339; R01HL109758-03 ( U.S. NIH Grant/Contract )
• First Posted: August 31, 2010
• Last Update Posted: August 24, 2021
• Last Verified: August 2021

Keywords provided by Vidu Garg, 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; exome sequencing; whole exome sequencing

Additional relevant MeSH terms:

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