Mosaicism in ASXL3-related syndrome: Description of five patients from three families

Eur J Med Genet. 2020 Jun;63(6):103925. doi: 10.1016/j.ejmg.2020.103925. Epub 2020 Mar 30.


De novo pathogenic variants in the additional sex combs-like 3 (ASXL3) gene cause a rare multi-systemic neurodevelopmental disorder. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. There is one previous report of ASXL3-related syndrome caused by de novo pathogenic variants in two siblings suggesting gonadal mosaicism. In this report, we present five patients with ASXL3-related syndrome, describing two families comprising two non-twin siblings harbouring apparent de novo pathogenic variants in ASXL3. Parents were clinically unaffected and there was no evidence of mosaicism from genomic DNA on exome-trio data, suggesting germline mosaicism in one of the parents. We also describe clinical details of a patient with typical features of ASXL3-related syndrome and mosaic de novo pathogenic variant in ASXL3 in 30-35% of both blood and saliva sample on trio-exome sequencing. We expand the known genetic basis of ASXL3-related syndromes and discuss mosaicism as a disease mechanism in five patients from three unrelated families. The findings of this report highlight the importance of taking gonadal mosaicism into consideration when counselling families regarding recurrence risk. We also discuss postzygotic mosaicism as a cause of fully penetrant ASXL3-related syndrome.

Publication types

  • Case Reports

MeSH terms

  • Child
  • Child, Preschool
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / pathology
  • Female
  • Humans
  • Male
  • Mosaicism*
  • Mutation
  • Pedigree
  • Transcription Factors / genetics*


  • ASXL3 protein, human
  • Transcription Factors