Deletions in the 3′ part of the NFIX gene including a recurrent alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of marshall-smith syndrome

Denny Schanze, Dorothée Neubauer, Valerie Cormier-Daire, Marie Ange Delrue, Anne Dieux-Coeslier, Tomonobu Hasegawa, Eva E. Holmberg, Rainer Koenig, Gabriele Krueger, Ina Schanze, Eva Seemanova, Adam C. Shaw, Julie Vogt, Marianne Volleth, André Reis, Peter Meinecke, Raoul C.M. Hennekam, Martin Zenker

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13 Citations (Scopus)

Abstract

Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner.

Original languageEnglish
Pages (from-to)1092-1100
Number of pages9
JournalHuman mutation
Volume35
Issue number9
DOIs
Publication statusPublished - 2014 Sep

Keywords

  • Intellectual disability
  • Marshall-Smith syndrome
  • NFIX
  • Nonsense-mediated decay
  • Nuclear factor 1/X

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Schanze, D., Neubauer, D., Cormier-Daire, V., Delrue, M. A., Dieux-Coeslier, A., Hasegawa, T., Holmberg, E. E., Koenig, R., Krueger, G., Schanze, I., Seemanova, E., Shaw, A. C., Vogt, J., Volleth, M., Reis, A., Meinecke, P., Hennekam, R. C. M., & Zenker, M. (2014). Deletions in the 3′ part of the NFIX gene including a recurrent alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of marshall-smith syndrome. Human mutation, 35(9), 1092-1100. https://doi.org/10.1002/humu.22603