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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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© 2018 Springer Nature Publishing AG
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 Urheber:
Flöttmann, Ricarda1, Autor
Kragesteen, Bjørt K.1, Autor
Geuer, Sinje1, Autor
Socha, Magdalena, Autor
Allou, Lila1, Autor
Sowińska-Seidler, Anna, Autor
Bosquillon de Jarcy, Laure, Autor
Wagner, Johannes, Autor
Jamsheer, Aleksander, Autor
Oehl-Jaschkowitz, Barbara, Autor
Wittler, Lars2, Autor           
de Silva, Deepthi, Autor
Kurth, Ingo, Autor
Maya, Idit, Autor
Santos-Simarro, Fernando, Autor
Hülsemann, Wiebke, Autor
Klopocki, Eva, Autor
Mountford, Roger, Autor
Fryer, Alan, Autor
Borck, Guntram, Autor
Horn, Denise, AutorLapunzina, Pablo, AutorWilson, Meredith, AutorMascrez, Bénédicte, AutorDuboule, Denis, AutorMundlos, Stefan1, Autor           Spielmann, Malte3, Autor            mehr..
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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 Zusammenfassung: 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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Sprache(n): eng - English
 Datum: 2017-10-122018-06
 Publikationsstatus: Erschienen
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 Identifikatoren: DOI: 10.1038/gim.2017.154
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Titel: GENETICS IN MEDICINE
  Andere : Genet. Med.
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: Baltimore, MD : Williams & Wilkins
Seiten: 9 Band / Heft: 20 (6) Artikelnummer: - Start- / Endseite: 599 - 607 Identifikator: ISSN: 1098-3600
CoNE: https://pure.mpg.de/cone/journals/resource/954925610933