Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause

Clin Genet. 2014 Sep;86(3):246-51. doi: 10.1111/cge.12259. Epub 2013 Sep 12.


Nager syndrome belongs to the group of acrofacial dysostosis, which are characterized by the association of craniofacial and limb malformations. Recently, exome sequencing studies identified the SF3B4 gene as the cause of this condition in most patients. SF3B4 encodes a highly conserved protein implicated in mRNA splicing and bone morphogenic protein (BMP) signaling. We performed SF3B4 sequencing in 14 families (18 patients) whose features were suggestive of Nager syndrome and found nine mutations predicted to result in loss-of-function. SF3B4 is the major gene responsible for autosomal dominant Nager syndrome. All mutations reported predict null alleles, therefore precluding genotype-phenotype correlations. Most mutation-negative patients were phenotypically indistinguishable from patients with mutations, suggesting genetic heterogeneity.

Keywords: Nager syndrome; SF3B4; acro-facial dysostosis; spliceosome.

MeSH terms

  • Base Sequence
  • Female
  • Genes, Dominant / genetics
  • Genetic Predisposition to Disease / genetics*
  • Haploinsufficiency / genetics*
  • Humans
  • Male
  • Mandibulofacial Dysostosis / genetics*
  • Mandibulofacial Dysostosis / pathology
  • Molecular Sequence Data
  • Mutation / genetics
  • Phenotype*
  • RNA Splicing Factors
  • RNA-Binding Proteins / genetics*
  • Sequence Analysis, DNA


  • RNA Splicing Factors
  • RNA-Binding Proteins
  • SF3B4 protein, human

Supplementary concepts

  • Acrofacial dysostosis, Nager type