Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy

Nat Commun. 2020 Jul 23;11(1):3698. doi: 10.1038/s41467-020-17452-6.


Intellectual disability (ID) is a heterogeneous clinical entity and includes an excess of males who harbor variants on the X-chromosome (XLID). We report rare FAM50A missense variants in the original Armfield XLID syndrome family localized in Xq28 and four additional unrelated males with overlapping features. Our fam50a knockout (KO) zebrafish model exhibits abnormal neurogenesis and craniofacial patterning, and in vivo complementation assays indicate that the patient-derived variants are hypomorphic. RNA sequencing analysis from fam50a KO zebrafish show dysregulation of the transcriptome, with augmented spliceosome mRNAs and depletion of transcripts involved in neurodevelopment. Zebrafish RNA-seq datasets show a preponderance of 3' alternative splicing events in fam50a KO, suggesting a role in the spliceosome C complex. These data are supported with transcriptomic signatures from cell lines derived from affected individuals and FAM50A protein-protein interaction data. In sum, Armfield XLID syndrome is a spliceosomopathy associated with aberrant mRNA processing during development.

Publication types

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

MeSH terms

  • Adult
  • Animals
  • Cell Nucleus / metabolism
  • Child
  • Child, Preschool
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Family
  • Female
  • Gene Expression Regulation, Developmental
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Mental Retardation, X-Linked / genetics*
  • Mice
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • NIH 3T3 Cells
  • Pedigree
  • Phenotype
  • Protein Transport
  • RNA Splicing / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Nuclear / genetics
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Spliceosomes / metabolism*
  • Syndrome
  • Zebrafish / genetics
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism


  • DNA-Binding Proteins
  • FAM50A protein, human
  • RNA, Messenger
  • RNA, Small Nuclear
  • RNA-Binding Proteins
  • U5 small nuclear RNA
  • Zebrafish Proteins
  • fam50a protein, zebrafish