Human Genetics of Truncus Arteriosus
Human genetic studies have revealed that truncus arteriosus is highly associated with 22q11.2 deletion syndrome. Other congenital malformation syndromes and mutations in genes encoding NKX and GATA transcription factors have also been reported as its etio
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Hiroyuki Yamagishi
Contents 47.1 47.2
Introduction Genetics 47.2.1 Syndromes and Chromosomal Anomalies 47.2.2 22q11.2 Deletion Syndrome (22q11DS) 47.2.3 Other Syndromes 47.2.4 Gene Mutations Conclusion References
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Abstract
Human genetic studies have revealed that truncus arteriosus is highly associated with 22q11.2 deletion syndrome. Other congenital malformation syndromes and mutations in genes encoding NKX and GATA transcription factors have also been reported as its etiology.
47.1
Introduction
Truncus arteriosus (TA) is an uncommon congenital heart defect (CHD) that results from complete failure of aorticopulmonary septum formation. Embryologically, ablation of cardiac neural crest cells (CNCC) leads to failure of partitioning the H. Yamagishi Division of Pediatric Cardiology, Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan e-mail: [email protected] © Springer-Verlag Wien 2016 S. Rickert-Sperling et al. (eds.), Congenital Heart Diseases: The Broken Heart: Clinical Features, Human Genetics and Molecular Pathways, DOI 10.1007/978-3-7091-1883-2_47
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H. Yamagishi
embryonic truncus arteriosus and disrupts conotruncal development by interfering with addition of the myocardium derived from the second heart field (SHF) (Fig. 47.1), resulting in TA [1]. The etiology of most patients with TA is usually unknown, and it is considered to be heterogenous and multifactorial in nature. Approximately 60 % of TA occurs as an isolated cardiovascular malformation, while the remainder has additional extracardiac anomalies and is frequently syndromic [2]. A diabetic mother has an increased risk of developing TA compared with the infant of a nondiabetic mother [2, 3]. A typical pattern of malformation was reported in embryos exposed to retinoic acid involving conotruncal and aortic arch anomalies including TA [2, 3].
Fig. 47.1 Cellular and molecular basis for normal and abnormal outflow tract development of the heart. The interaction of progenitor cells derived from the second heart field (SHF cells) and the cardiac neural crest (CNCC) that give rise to the outflow tract (OFT) myocardium and septum, respectively, plays a key role in the development of the OFT. TBX1, a major genetic determinant of the 22q11.2 deletion syndrome (22q11DS), is exclusively expressed in the SHF cells. TBX1 deletion in 22q11DS may affect not only the SHF cells but also the interaction of the SHF cells and CNCC and result in OFT defects ranging from tetralogy of Fallot, which is characterized by malalignment of the OFT septum, to truncus arteriosus, which results from aplasia of the OFT septum
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Human Genetics of Truncus Arteriosus
Several genes encoding transcription factors and signaling proteins highlight the importance of the CNCC and SHF and their interaction [4]. Mice deficient for genes encoding these proteins result in TA. Syndromes with chromosome 22q11.2 microdeletion served as an entry to understanding the genetic basis for TA, and a gene encoding the transcrip
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