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  Rare and Private Variations in Neural Crest, Apoptosis and Sarcomere Genes Define the Polygenic Background of Isolated Tetralogy of Fallot

Grunert, M., Dorn, C., Schueler, M., Dunkel, I., Schlesinger, J., Mebus, S., et al. (2014). Rare and Private Variations in Neural Crest, Apoptosis and Sarcomere Genes Define the Polygenic Background of Isolated Tetralogy of Fallot. Human Molecular Genetics, 23(12), 3115-3128. doi:10.1093/hmg/ddu021.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-A88F-C Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-A890-6
Genre: Journal Article

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 Creators:
Grunert, Marcel1, Author              
Dorn, Cornelia1, Author              
Schueler, Markus1, Author              
Dunkel, Ilona2, Author              
Schlesinger, Jenny1, Author              
Mebus, Siegrun, Author
Alexi-Meskishvili, Vladimir, Author
Perrot, Andreas, Author
Wassilew, Katharina, Author
Timmermann, Bernd3, Author              
Hetzer, Roland, Author
Berger, Felix, Author
Sperling, Silke R.1, Author              
Affiliations:
1Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              
2Computational Epigenetics (Ho-Ryun Chung), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479658              
3Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              

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 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.

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Language(s): eng - English
 Dates: 2014-01-192014-01-232014-06-15
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1093/hmg/ddu021
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Title: Human Molecular Genetics
Source Genre: Journal
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Publ. Info: Oxford, England : IRL Press
Pages: - Volume / Issue: 23 (12) Sequence Number: - Start / End Page: 3115 - 3128 Identifier: ISSN: 0964-6906
CoNE: /journals/resource/954925581153