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  Noncoding copy-number variations are associated with congenital limb malformation

Flöttmann, R., Kragesteen, B. K., Geuer, S., Socha, M., Allou, L., Sowińska-Seidler, A., et al. (2018). Noncoding copy-number variations are associated with congenital limb malformation. GENETICS IN MEDICINE, 20(6), 599-607. doi:10.1038/gim.2017.154.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-5C96-D Version Permalink: http://hdl.handle.net/21.11116/0000-0003-5C97-C
Genre: Journal Article

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 Creators:
Flöttmann, Ricarda1, Author
Kragesteen, Bjørt K.1, Author
Geuer, Sinje1, Author
Socha, Magdalena, Author
Allou, Lila1, Author
Sowińska-Seidler, Anna, Author
Bosquillon de Jarcy, Laure, Author
Wagner, Johannes, Author
Jamsheer, Aleksander, Author
Oehl-Jaschkowitz, Barbara, Author
Wittler, Lars2, Author              
de Silva, Deepthi, Author
Kurth, Ingo, Author
Maya, Idit, Author
Santos-Simarro, Fernando, Author
Hülsemann, Wiebke, Author
Klopocki, Eva, Author
Mountford, Roger, Author
Fryer, Alan, Author
Borck, Guntram, Author
Horn, Denise, AuthorLapunzina, Pablo, AuthorWilson, Meredith, AuthorMascrez, Bénédicte, AuthorDuboule, Denis, AuthorMundlos, Stefan1, Author              Spielmann, Malte3, Author               more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
3Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014183              

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 Abstract: PurposeCopy-number variants (CNVs) are generally interpreted by linking the effects of gene dosage with phenotypes. The clinical interpretation of noncoding CNVs remains challenging. We investigated the percentage of disease-associated CNVs in patients with congenital limb malformations that affect noncoding cis-regulatory sequences versus genes sensitive to gene dosage effects.MethodsWe applied high-resolution copy-number analysis to 340 unrelated individuals with isolated limb malformation. To investigate novel candidate CNVs, we re-engineered human CNVs in mice using clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing.ResultsOf the individuals studied, 10% harbored CNVs segregating with the phenotype in the affected families. We identified 31 CNVs previously associated with congenital limb malformations and four novel candidate CNVs. Most of the disease-associated CNVs (57%) affected the noncoding cis-regulatory genome, while only 43% included a known disease gene and were likely to result from gene dosage effects. In transgenic mice harboring four novel candidate CNVs, we observed altered gene expression in all cases, indicating that the CNVs had a regulatory effect either by changing the enhancer dosage or altering the topological associating domain architecture of the genome.ConclusionOur findings suggest that CNVs affecting noncoding regulatory elements are a major cause of congenital limb malformations.

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Language(s): eng - English
 Dates: 2017-10-122018-06
 Publication Status: Published in print
 Pages: -
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 Identifiers: DOI: 10.1038/gim.2017.154
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Title: GENETICS IN MEDICINE
  Other : Genet. Med.
Source Genre: Journal
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Publ. Info: Baltimore, MD : Williams & Wilkins
Pages: 9 Volume / Issue: 20 (6) Sequence Number: - Start / End Page: 599 - 607 Identifier: ISSN: 1098-3600
CoNE: https://pure.mpg.de/cone/journals/resource/954925610933