English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT

Released

Journal Article

Noncoding copy-number variations are associated with congenital limb malformation

MPS-Authors

Flöttmann,  Ricarda
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Kragesteen,  Bjørt K.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Geuer,  Sinje
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Allou,  Lila
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons50647

Wittler,  Lars
Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons50437

Mundlos,  Stefan
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons50565

Spielmann,  Malte
Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Locator
There are no locators available
Fulltext (public)

Flöttmann.pdf
(Publisher version), 2MB

Supplementary Material (public)
There is no public supplementary material available
Citation

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.


Cite as: http://hdl.handle.net/21.11116/0000-0003-5C96-D
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.