EFTUD2 missense variants disrupt protein function and splicing in Mandibulofacial Dysostosis Guion-Almeida type

Huw Thomas, Katherine Wood, Weronika Buczek, Christopher Gordon, Veronique Pingault, Tania Attie-Bitach, Kathryn Hentges, Vinod Varghese, Jeanne Amiel, William Newman, Raymond O'Keefe

Research output: Contribution to journalArticlepeer-review


Pathogenic variants in the core spliceosome U5 snRNP gene EFTUD2/SNU114 cause the craniofacial disorder Mandibulofacial Dysostosis Guion-Almeida type (MFDGA). MFDGA-associated variants in EFTUD2 comprise large deletions encompassing EFTUD2, intragenic deletions and single nucleotide truncating or missense variants. These variants are predicted to result in haploinsufficiency by loss-of-function of the variant allele. While the contribution of deletions within EFTUD2 to allele loss-of-function are self-evident, the mechanisms by which missense variants are disease-causing have not been characterised functionally. Combining bioinformatics software prediction, yeast functional growth assays and a minigene splicing assay, we have characterised how MFDGA missense variants result in EFTUD2 loss-of-function. Only four of 19 assessed missense variants cause EFTUD2 loss-of-function through altered protein function when modelled in yeast. Of the remaining 15 missense variants, five altered the normal splicing pattern of EFTUD2 pre-mRNA predominantly through exon skipping or cryptic splice site activation, leading to the introduction of a premature termination codon. Comparison of bioinformatic predictors for each missense variant revealed a disparity amongst different software packages and, in many cases, an inability to correctly predict changes in splicing subsequently determined by minigene interrogation. This work highlights the need for laboratory-based validation of bioinformatic predictions for EFTUD2 missense variants.
Original languageEnglish
JournalHuman Mutation
Early online date25 Apr 2020
Publication statusPublished - 3 May 2020


  • EFTUD2
  • Snu114
  • Pre-mRNA splicing
  • splicing variants
  • minigene
  • Mandibulofacial Dysostosis Guion-Almeida type
  • missense variants
  • yeast


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