Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity

Eur J Hum Genet. 2021 Apr;29(4):593-603. doi: 10.1038/s41431-020-00766-w. Epub 2020 Nov 22.


ABL1 is a proto-oncogene encoding a nonreceptor tyrosine kinase, best known in the somatic BCR-ABL fusion gene associated with chronic myeloid leukaemia. Recently, germline missense variants in ABL1 have been found to cause an autosomal dominant developmental syndrome with congenital heart disease, skeletal malformations and characteristic facies. Here, we describe a series of six new unrelated individuals with heterozygous missense variants in ABL1 (including four novel variants) identified via whole exome sequencing. All the affected individuals in this series recapitulate the phenotype of the ABL1 developmental syndrome and additionally we affirm that hearing impairment is a common feature of the condition. Four of the variants cluster in the myristoyl-binding pocket of ABL1, a region critical for auto-inhibitory regulation of the kinase domain. Bio-informatic analysis of transcript-wide conservation and germline/somatic variation reveals that this pocket region is subject to high missense constraint and evolutionary conservation. Functional work to investigate ABL1 kinase activity in vitro by transient transfection of HEK293T cells with variant ABL1 plasmid constructs revealed increased phosphorylation of ABL1-specific substrates compared to wild-type. The increased tyrosine kinase activity was suppressed by imatinib treatment. This case series of six new patients with germline heterozygous ABL1 missense variants further delineates the phenotypic spectrum of this condition and recognises microcephaly as a common finding. Our analysis supports an ABL1 gain-of-function mechanism due to loss of auto-inhibition, and demonstrates the potential for pharmacological inhibition using imatinib.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Binding Sites
  • Child
  • Child, Preschool
  • Female
  • Foot Deformities / genetics*
  • Foot Deformities / pathology
  • HEK293 Cells
  • Hand Deformities / genetics*
  • Hand Deformities / pathology
  • Hearing Loss / genetics*
  • Hearing Loss / pathology
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / pathology
  • Humans
  • Male
  • Mutation, Missense
  • Myristic Acid / metabolism
  • Phenotype
  • Protein Binding
  • Proto-Oncogene Proteins c-abl / chemistry
  • Proto-Oncogene Proteins c-abl / genetics*
  • Proto-Oncogene Proteins c-abl / metabolism
  • Syndrome


  • Myristic Acid
  • ABL1 protein, human
  • Proto-Oncogene Proteins c-abl