Tuesday, May 10, 2022

TBCK mutations

Inspired by sibling patients

Guerreiro RJ, Brown R, Dian D, de Goede C, Bras J, Mole SE. Mutation of TBCK causes a rare recessive developmental disorder. Neurol Genet. 2016 May 24;2(3):e76. doi: 10.1212/NXG.0000000000000076. Erratum in: Neurol Genet. 2016 Aug 04;2(4):e86. PMID: 27275012; PMCID: PMC4881620


Objective: To characterize the underlying genetic defect in a family with 3 siblings affected by a severe, yet viable, congenital disorder.

Methods: Extensive genetic and metabolic investigations were performed, and the affected children were imaged at different ages. Whole-genome genotyping and whole-exome sequencing were undertaken. A single large region (>8 Mb) of homozygosity in chromosome 4 (chr4:100,268,553-108,609,628) was identified that was shared only in affected siblings. Inspection of genetic variability within this region led to the identification of a novel mutation. Sanger sequencing confirmed segregation of the mutation with disease.

Results: All affected siblings share homozygosity for a novel 4-bp deletion in the gene TBCK (NM_033115:c.614_617del:p.205_206del).

Conclusions: This finding provides the genetic cause of a severe inherited disease in a family and extends the number of mutations and phenotypes associated with this recently identified disease gene.

Zapata-Aldana E, Kim DD, Remtulla S, Prasad C, Nguyen CT, Campbell C. 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. PMID: 30103036.


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.

Mandel H, Khayat M, Chervinsky E, Elpeleg O, Shalev S. TBCK-related intellectual disability syndrome: Case study of two patients. Am J Med Genet A. 2017 Feb;173(2):491-494. doi: 10.1002/ajmg.a.38019. Epub 2016 Oct 17. PMID: 27748029.


There is a significant level of genetic heterogeneity underlying the phenotype of nonspecific hypotonia with severe intellectual disability. Exome sequencing has proven to be a powerful tool for identifying the underlying molecular basis of such nonspecific, abnormal neurological phenotypes. Mutations in the TBCK gene have been reported associated with very poor, if any, psychomotor development, poor speech, and inability to walk independently. We describe the long-term phenotypic evolution of a severe nonspecific neurodevelopmental disorder in two siblings born to an Arab-Moslem family living in northern Israel. Exome sequencing led to identification of a novel homozygous mutation: c.1854delT in the TBCK gene. Abnormal elevated β-HCG was found in the maternal serum during the two pregnancies, a finding that has not been reported before. These individuals present with severe intellectual disability, no speech, hypotonia, convulsions, and lack of any independent daily skills. 

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