Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome

Am J Hum Genet. 2012 May 4;90(5):925-33. doi: 10.1016/j.ajhg.2012.04.004. Epub 2012 Apr 26.


Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings add Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • Child, Preschool
  • Cohort Studies
  • Exome
  • Female
  • Haploinsufficiency
  • Humans
  • Limb Deformities, Congenital / genetics
  • Limb Deformities, Congenital / physiopathology
  • Male
  • Mandibulofacial Dysostosis / genetics*
  • Mandibulofacial Dysostosis / physiopathology
  • Mutation
  • RNA Precursors / genetics*
  • RNA Precursors / metabolism
  • RNA Splicing Factors
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Reproducibility of Results
  • Spliceosomes / genetics*
  • Young Adult


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

Supplementary concepts

  • Acrofacial dysostosis, Nager type