Nager syndrome in patient lacking acrofacial dysostosis: Expanding the phenotypic spectrum of SF3B4-related disease

Am J Med Genet A. 2021 May;185(5):1515-1518. doi: 10.1002/ajmg.a.62113. Epub 2021 Feb 8.


Nager syndrome epitomizes the acrofacial dysostoses, which are characterized by craniofacial and limb defects. The craniofacial defects include midfacial retrusion, downslanting palpebral fissures, prominent nasal bridge, and micrognathia. Limb malformations typically include hypoplasia or aplasia of radial elements including the thumb. Nager syndrome is caused by haploinsufficiency of SF3B4, encoding a spliceosomal protein called SAP49. Here, we report a patient with a loss of function variant in SF3B4 without acrofacial dysostosis or limb defects, whose reason for referral was developmental and growth delay. This patient is evidence of a broader phenotypic spectrum associated with SF3B4 variants than previously appreciated.

Keywords: Nager syndrome; SF3B4; acrofacial dysostosis; exome sequencing; spliceosome.

Publication types

  • Case Reports

MeSH terms

  • Craniofacial Dysostosis / genetics
  • Craniofacial Dysostosis / pathology
  • Genetic Predisposition to Disease*
  • Haploinsufficiency / genetics
  • Humans
  • Infant
  • Limb Deformities, Congenital / genetics
  • Limb Deformities, Congenital / pathology
  • Male
  • Mandibulofacial Dysostosis / genetics*
  • Mandibulofacial Dysostosis / pathology
  • Mutation / genetics
  • Phenotype
  • RNA Splicing Factors / genetics*
  • Spliceosomes / genetics*
  • Spliceosomes / pathology


  • RNA Splicing Factors
  • SF3B4 protein, human

Supplementary concepts

  • Acrofacial dysostosis, Nager type