Further delineation of TBCK - Infantile hypotonia with psychomotor retardation and characteristic facies type 3

Eur J Med Genet. 2019 Apr;62(4):273-277. doi: 10.1016/j.ejmg.2018.08.004. Epub 2018 Aug 11.


Deleterious homozygous or compound heterozygous mutations in the TBCK (TBC1-domain-containing kinase) gene (implicated in the MTOR pathway) produce profound hypotonia, global developmental delay, facial dysmorphic features, and brain abnormalities. The disorder has been named "infantile hypotonia with psychomotor retardation and characteristic facies-3" (IHPRF3). Here we present two sisters with a novel mutation in TBCK (NM_001163435.2: c.753dup; p.(Lys252*)) who have this ultrarare disorder. We have reviewed the literature on the 33 previously reported cases to provide a characterization of this emerging phenotype. Pathogenic mutations in TBCK have a predominant involvement of the Central Nervous System with a progressive pattern, leading to the conclusion where pathogenic mutations of the said gene lead to a progressive neurodegenerative disease. This report adds novel mutation and features to this complex phenotype. Further investigation is required to understand the pathogenesis of TBCK.

Keywords: Cerebellar hypoplasia; Hypotonia; IHPRF3; MTOR; TBCK.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Child
  • Child, Preschool
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / pathology
  • Facies*
  • Female
  • Humans
  • Loss of Function Mutation
  • Muscle Hypotonia / genetics*
  • Muscle Hypotonia / pathology
  • Phenotype*
  • Protein Serine-Threonine Kinases / genetics*
  • Reflex, Stretch
  • Siblings


  • Protein Serine-Threonine Kinases
  • TBCK protein, human