Genetics of Congenital Heart Disease
| Status: | Recruiting |
|---|---|
| Conditions: | Peripheral Vascular Disease, Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 3/22/2019 |
| Start Date: | December 2009 |
| End Date: | December 2025 |
| Contact: | Vidu Garg, MD |
| Email: | vidu.garg@nationwidechildrens.org |
| Phone: | 614-355-5710 |
Genetics Testing of Individuals and Families With Congenital Heart Disease
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.
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.
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.
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.
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
We found this trial at
1
site
700 Childrens Drive
Columbus, Ohio 43205
Columbus, Ohio 43205
(616) 722-2000
Principal Investigator: Vidu Garg, MD
Nationwide Children's Hospital At Nationwide Children’s, we are creating the future of pediatric health care....
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