Noncoding copy-number variations are associated with congenital limb malformation

Ricarda Flöttmann, Bjørt K. Kragesteen, Sinje Geuer, Magdalena Socha, Lila Allou, Anna Sowińska-Seidler, Laure Bosquillon De Jarcy, Johannes Wagner, Aleksander Jamsheer, Barbara Oehl-Jaschkowitz, Lars Wittler, Deepthi De Silva, Ingo Kurth, Idit Maya, Fernando Santos-Simarro, Wiebke Hülsemann, Eva Klopocki, Roger Mountford, Alan Fryer, Guntram BorckDenise Horn, Pablo Lapunzina, Meredith Wilson, Bénédicte Mascrez, Denis Duboule, Stefan Mundlos, Malte Spielmann*

*Corresponding author for this work
34 Citations (Scopus)


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.

Original languageEnglish
JournalGenetics in Medicine
Issue number6
Pages (from-to)599-607
Number of pages9
Publication statusPublished - 01.06.2018

Research Areas and Centers

  • Research Area: Medical Genetics
  • Centers: Center for Rare Diseases (ZSE)

DFG Research Classification Scheme

  • 205-03 Human Genetics


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