Genetics of 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. 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.

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).

cardiology clinic sample, community sample

• 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. Epub 2009 Feb 4. No abstract available.
• Maitra M, Koenig SN, Srivastava D, Garg V. Identification of GATA6 sequence variants in patients with congenital heart defects. Pediatr Res. 2010 Jun 24; [Epub ahead of print]
• 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. 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.
• 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.

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