Human Genetics of Defects of Situs
Defects of situs are associated with complex sets of congenital heart defects in which the normal concordance of asymmetric thoracic and abdominal organs is disturbed. The cellular and molecular mechanisms underlying the formation of the embryonic left-ri
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Andreas Perrot and Silke Rickert-Sperling
Contents 38.1 38.2 38.3
Introduction ................................................................................................................... Copy Number Variations............................................................................................... Single Gene Defects ...................................................................................................... 38.3.1 Cardiac Transcription Factors 38.3.2 Genes Involved in TGFβ Signaling Pathways 38.3.3 Histone-Modifying Genes 38.3.4 Ciliary Genes 38.3.5 Other Genes Conclusion ............................................................................................................................... References ................................................................................................................................
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Abstract
Defects of situs are associated with complex sets of congenital heart defects in which the normal concordance of asymmetric thoracic and abdominal organs is disturbed. The cellular and molecular mechanisms underlying the formation of the embryonic left-right axis have been investigated extensively in the past decade. This has led to the identification of mutations in at least 24 different genes in humans with heterotaxy and situs defects. Those mutations affect a broad range of molecular components, from transcription factors, signaling molecules, and chromatin modifiers to ciliary proteins. A substantial overlap of these genes is observed with genes associated with other congenital heart diseases such as tetralogy of
A. Perrot • S. Rickert-Sperling (*) Cardiovascular Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany 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_38
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A. Perrot and S. Rickert-Sperling
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Fallot and double outlet right ventricle, d-transposition of the great arteries, and atrioventricular septal defects. In this chapter, we present the broad genetic heterogeneity of situs defects including recent human genomics efforts.
38.1
Introduction
Situs inversus is found in about 0.01 % of the population, or about 1 person in 10,000. In the most common situation, the relationship between the organs is unchanged, and most people with situs inversus have no medical symptoms or complications [1]. In cases of situs ambiguus, the arrangement of the thoracoabdominal organs across the left-right (LR) axis of the body is variable. Frequently, the term heterotaxy is used synonymously for situs ambiguus. This broad term includes patients with a wide variety of very complex cardiac lesions. A right-sided heart position is called dextroposition. If the apex of the heart points to the right, it is called dextrocardia. Heterotaxy shows a high 79 % recurrence risk ratio among first-degree relatives, which und
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