Genetics of Congenital Heart Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2015 by Nationwide Children's Hospital
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Vidu Garg, Nationwide Children's Hospital
ClinicalTrials.gov Identifier:
NCT01192048
First received: August 30, 2010
Last updated: June 29, 2015
Last verified: June 2015
  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. 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 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 ] [ Designated as safety issue: No ]
    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 datapipeline (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.

  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:

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
Study First Received: August 30, 2010
Last Updated: June 29, 2015
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
exome sequencing
whole exome sequencing

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

ClinicalTrials.gov processed this record on August 02, 2015