Advances in molecular genetics of congenital heart disease.

See article on pageS 263-72 While congenital heart diseases (CHD) are common causes of mortality and morbidity in infants and children, the basic underlying genetic and molecular mechanisms have remained largely undetermined. Breakthroughs in molecular genetic technology have just begun to be applied in pediatric cardiology stemming from the use of chromosomal mapping and the identification of genes involved in both the primary etiology and as significant risk factors in the development of cardiac and vascular abnormalities. These advances have been applied to study families with several affected individuals, providing new insights into the genetic basis of a number of CHD, including ventricular septal defect (VSD). Moreover, developing new technology may offer a great opportunity for further advancement in genetic diagnostics and for the future of gene therapy. Increasing evidence suggests that single gene mutations are present in a broad spectrum of genes involved in cardiac structure and function. Pleiotropic cardiac malformations can result from discrete mutations in specific nuclear transcription factors, proteins recognized as playing key regulatory roles during cardiovascular development and morphogenesis. 1,2 Factors such as GATA4, Nkx2.5, dHAND, TFAP2, and Tbx5 are among the earliest transcription factors expressed in the developing heart and are crucial in the activation of cardiac-specific genes. Mutations in each of these genes result in severe cardiac abnormalities including septal defects (GATA4), conduction defects (NKX2-5), right ventricular hypoplasia (HAND2), patent ductus arteriosus (PDA) in Char syndrome (TFAP2B), and Holt-Oram syndrome (TBX5) underscoring the critical role played by the disruption of early heart development and morphogenesis in the genesis of CHD. Genetic defects in proteins involved in the multiple signaling pathways that modulate cell proliferation, migration and differentiation in early cardiovascular development have also been identified. Mutations in JAG1 have been found in kindred studies in association with Alagille syndrome, a complex autosomal-dominant disorder presenting with CHD including pulmonary artery stenosis and tetralogy of Fallot (TOF). 7 JAG1 encodes a ligand that binds the Notch receptor, an evolutionarily conserved signaling pathway involved in cell fate specification. Mutations in the signaling regulator Notch1 have recently been implicated in aortic valve disease. 8 Mutations in PTPN11 encoding a protein tyrosine-phosphatase (SHP-2) have been proposed to play a role in the pathogenesis of Noonan syndrome characterized by conduction defects, pulmonary stenosis, and hypertrophic cardiomyopathy, 9 and have been also recently implicated in the pathogenesis of LEOPARD syndrome, which likely represents an allelic disorder. 10 Specific cardiac malformations …