Rare and private variations in neural crest, apoptosis and sarcomere genes define the polygenic background of isolated Tetralogy of Fallot

Item Type:	Article
Title:	Rare and private variations in neural crest, apoptosis and sarcomere genes define the polygenic background of isolated Tetralogy of Fallot
Creators Name:	Grunert, M. and Dorn, C. and Schueler, M. and Dunkel, I. and Schlesinger, J. and Mebus, S. and Alexi-Meskishvili, V. and Perrot, A. and Wassilew, K. and Timmermann, B. and Hetzer, R. and Berger, F. and Sperling, S.R.
Abstract:	Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Its genetic basis is demonstrated by an increased recurrence risk in siblings and familial cases. However, the majority of TOF are sporadic isolated cases of undefined origin and it had been postulated that rare and private autosomal variations in concert define its genetic basis. To elucidate this hypothesis we performed a multilevel study using targeted re-sequencing and whole-transcriptome profiling. We developed a novel concept based on a gene's mutation frequency to unravel the polygenic origin of TOF. We show that isolated TOF is caused by a combination of deleterious private and rare mutations in genes essential for apoptosis and cell growth, the assembly of the sarcomere as well as for the neural crest and secondary heart field, the cellular basis of the right ventricle and its outflow tract. Affected genes coincide in an interaction network with significant disturbances in expression shared by cases with a mutually affected TOF gene. The majority of genes show continuous expression during adulthood, which opens a new route to understand the diversity in the long-term clinical outcome of TOF cases. Our findings demonstrate that TOF has a polygenic origin and that understanding the genetic basis can lead to novel diagnostic and therapeutic routes. Moreover, the novel concept of the gene mutation frequency is a versatile measure and can be applied to other open genetic disorders.
Keywords:	Apoptosis, Base Sequence, Cell Proliferation, Cohort Studies, DNA Sequence Analysis, Gene Expression Profiling, Gene Expression Regulation, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Molecular Sequence Data, Multifactorial Inheritance, Mutation, Myocardium, Tetralogy of Fallot
Source:	Human Molecular Genetics
ISSN:	0964-6906
Publisher:	Oxford University Press
Volume:	23
Number:	12
Page Range:	3115-3128
Date:	15 June 2014
Official Publication:	https://doi.org/10.1093/hmg/ddu021
PubMed:	View item in PubMed

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