Genetics of Congenital Heart Disease

NCT01192048 | Recruiting

• 2 other identifiers: IRB09-00339R01HL109758
• Study Type: observational
• Target: 1,000
• Locations: 1 country
• Sites: 1

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

Conditions

Congenital Heart Disease

Keywords

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; whole genome sequencing

Outcome Measures

Primary Outcomes (1)

• Identification of novel genetic contributors to congenital heart defects

  Novel genetic abnormalities that are found to be associated with congenital heart defects in humans

  up to 3 years, from date of genetic analysis to completion of genetic data analysis or identification of novel genetic contributors, whichever comes first

Study Arms (1)

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

Interventions

Blood Sample Collection OTHER

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

Study Subjects

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

cardiology clinic sample, community sample

You may qualify if:

• Subjects must have a diagnosis of Congenital Heart Disease or be related to individuals with Congenital Heart Disease.

You may not qualify if:

• Healthy individuals unrelated to those with Congenital Heart Disease

Sponsors & Collaborators

• Nationwide Children's Hospital: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

RECRUITING

Related Publications (15)

• 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. No abstract available.

  PMID: 19328042 BACKGROUND

• 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/PDR.0b013e3181ed17e4.

  PMID: 20581743 BACKGROUND

• 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. doi: 10.1002/ajmg.a.31652.

  PMID: 17352393 BACKGROUND

• 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. doi: 10.1038/nature03940. Epub 2005 Jul 17.

  PMID: 16025100 BACKGROUND

• 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. doi: 10.1038/nature01827. Epub 2003 Jul 6.

  PMID: 12845333 BACKGROUND

• 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.

  PMID: 24796370 BACKGROUND

• 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.

  PMID: 25260786 BACKGROUND

• 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.

  PMID: 27418595 BACKGROUND

• Bennett JS, Gordon DM, Majumdar U, Lawrence PJ, Matos-Nieves A, Myers K, Kamp AN, Leonard JC, McBride KL, White P, Garg V. Use of machine learning to classify high-risk variants of uncertain significance in lamin A/C cardiac disease. Heart Rhythm. 2022 Apr;19(4):676-685. doi: 10.1016/j.hrthm.2021.12.019. Epub 2021 Dec 24.

  PMID: 34958940 BACKGROUND

• Yasuhara J, Garg V. Genetics of congenital heart disease: a narrative review of recent advances and clinical implications. Transl Pediatr. 2021 Sep;10(9):2366-2386. doi: 10.21037/tp-21-297.

  PMID: 34733677 BACKGROUND

• Choudhury TZ, Garg V. Molecular genetic mechanisms of congenital heart disease. Curr Opin Genet Dev. 2022 Aug;75:101949. doi: 10.1016/j.gde.2022.101949. Epub 2022 Jul 8.

  PMID: 35816939 BACKGROUND

• Chang SW, Mislankar M, Misra C, Huang N, Dajusta DG, Harrison SM, McBride KL, Baker LA, Garg V. Genetic abnormalities in FOXP1 are associated with congenital heart defects. Hum Mutat. 2013 Sep;34(9):1226-30. doi: 10.1002/humu.22366. Epub 2013 Jul 11.

  PMID: 23766104 BACKGROUND

• Yasuhara J, Manivannan SN, Majumdar U, Gordon DM, Lawrence PJ, Aljuhani M, Myers K, Stiver C, Bigelow AM, Galantowicz M, Yamagishi H, McBride KL, White P, Garg V. Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis. Pediatr Res. 2024 Jan;95(1):146-155. doi: 10.1038/s41390-023-02811-y. Epub 2023 Sep 12.

  PMID: 37700164 BACKGROUND

• Gordon DM, Cunningham D, Zender G, Lawrence PJ, Penaloza JS, Lin H, Fitzgerald-Butt SM, Myers K, Duong T, Corsmeier DJ, Gaither JB, Kuck HC, Wijeratne S, Moreland B, Kelly BJ; Baylor-Johns Hopkins Center for Mendelian Genomics; Garg V, White P, McBride KL. Exome sequencing in multiplex families with left-sided cardiac defects has high yield for disease gene discovery. PLoS Genet. 2022 Jun 23;18(6):e1010236. doi: 10.1371/journal.pgen.1010236. eCollection 2022 Jun.

  PMID: 35737725 BACKGROUND

• Manivannan SN, Darouich S, Masmoudi A, Gordon D, Zender G, Han Z, Fitzgerald-Butt S, White P, McBride KL, Kharrat M, Garg V. Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy. PLoS Genet. 2020 May 26;16(5):e1008639. doi: 10.1371/journal.pgen.1008639. eCollection 2020 May.

  PMID: 32453731 BACKGROUND

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.

MeSH Terms

Conditions

Heart Defects, Congenital; Congenital Abnormalities

Condition Hierarchy (Ancestors)

Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Vidu Garg, MD

  The Research Institute at Nationwide Children's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Katherine M Spayde, MS, CGC

CONTACT

614-355-6388; katherine.spayde@nationwidechildrens.org

Study Design

• Study Type: observational
• Observational Model: FAMILY BASED
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director and Professor

Study Record Dates

• First Submitted: August 30, 2010
• First Posted: August 31, 2010
• Study Start: December 1, 2009
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: March 12, 2025

Record last verified: 2025-03

Locations

US (1)