A review of craniofacial disorders caused by spliceosomal defects

Clin Genet. 2015 Nov;88(5):405-15. doi: 10.1111/cge.12596. Epub 2015 May 1.


The spliceosome is a large ribonucleoprotein complex that removes introns from pre-mRNA transcripts. Mutations in EFTUD2, encoding a component of the major spliceosome, have recently been identified as the cause of mandibulofacial dysostosis, Guion-Almeida type (MFDGA), characterized by mandibulofacial dysostosis, microcephaly, external ear malformations and intellectual disability. Mutations in several other genes involved in spliceosomal function or linked aspects of mRNA processing have also recently been identified in human disorders with specific craniofacial malformations: SF3B4 in Nager syndrome, an acrofacial dysostosis (AFD); SNRPB in cerebrocostomandibular syndrome, characterized by Robin sequence and rib defects; EIF4A3 in the AFD Richieri-Costa-Pereira syndrome, characterized by Robin sequence, median mandibular cleft and limb defects; and TXNL4A in Burn-McKeown syndrome, involving specific craniofacial dysmorphisms. Here, we review phenotypic and molecular aspects of these syndromes. Given the apparent sensitivity of craniofacial development to defects in mRNA processing, it is possible that mutations in other proteins involved in spliceosomal function will emerge in the future as causative for related human disorders.

Keywords: congenital malformations; craniofacial; mandibulofacial dysostosis; spliceosome.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Choanal Atresia / genetics
  • Choanal Atresia / metabolism*
  • Clubfoot / genetics
  • Clubfoot / metabolism*
  • DEAD-box RNA Helicases / genetics
  • Deafness / congenital*
  • Deafness / genetics
  • Deafness / metabolism
  • Eukaryotic Initiation Factor-4A / genetics
  • Facies
  • Female
  • Hand Deformities, Congenital / genetics
  • Hand Deformities, Congenital / metabolism*
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / metabolism*
  • Humans
  • Intellectual Disability / genetics
  • Intellectual Disability / metabolism*
  • Male
  • Mandibulofacial Dysostosis / genetics
  • Mandibulofacial Dysostosis / metabolism*
  • Micrognathism / genetics
  • Micrognathism / metabolism*
  • Mutation*
  • Peptide Elongation Factors / genetics
  • Pierre Robin Syndrome / genetics
  • Pierre Robin Syndrome / metabolism*
  • RNA Splicing Factors
  • RNA-Binding Proteins / genetics
  • Ribonucleoprotein, U5 Small Nuclear / genetics
  • Ribs / abnormalities*
  • Ribs / metabolism
  • Spliceosomes / genetics
  • Spliceosomes / metabolism*


  • EFTUD2 protein, human
  • Peptide Elongation Factors
  • RNA Splicing Factors
  • RNA-Binding Proteins
  • Ribonucleoprotein, U5 Small Nuclear
  • SF3B4 protein, human
  • TXNL4A protein, human
  • Eukaryotic Initiation Factor-4A
  • EIF4A3 protein, human
  • DEAD-box RNA Helicases

Supplementary concepts

  • Burn-Mckeown syndrome
  • Cerebrocostomandibular Syndrome
  • Richieri Costa Pereira syndrome