Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia

Abstract

Through an international multi-center collaboration, 13 individuals from nine unrelated families and affected by likely pathogenic biallelic variants in TBC1-domain-containing kinase (TBCK) were identified through whole-exome sequencing. All affected individuals were found to share a core phenotype of intellectual disability and hypotonia, and many had seizures and showed brain atrophy and white-matter changes on neuroimaging. Minor non-specific facial dysmorphism was also noted in some individuals, including multiple older children who developed coarse features similar to those of storage disorders. TBCK has been shown to regulate the mammalian target of rapamycin (mTOR) signaling pathway, which is also stimulated by exogenous leucine supplementation. TBCK was absent in cells from affected individuals, and decreased phosphorylation of phospho-ribosomal protein S6 was also observed, a finding suggestive of downregulation of mTOR signaling. Lastly, we demonstrated that activation of the mTOR pathway in response to L-leucine supplementation was retained, suggesting a possible avenue for directed therapies for this condition.

Whole‐exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: Outcomes from a cohort of 50 families

“…In 1 additional family, we identified a novel disease-gene relationship, a new disease associated with a known gene, KIF1A, 14 and in 2 other families we identified the novel IPN genes, TBCK and MCM3AP. 13,19 Our diagnostic rate (24%) is within the 11% to 53% range of recently reported IPN cohorts ( Table 2) [4][5][6][7][8][9][10] ; and similar to the percentage of the total number of diagnoses in known genes in these IPN cohorts (29%; 102/354) ( Table 2). The wide range in diagnostic rates for these cohorts may be due to the use of different variant pathogenicity criteria and/or the number of genetic tests performed prior to WES; both make studies difficult to compare.…”

“…For example, interrogation of the WES data-set in this study resulted in 3 discoveries within our cohort; a novel disease associated with the gene KIF1A, 14 and 2 novel diseasecausing genes, TBCK and MCM3AP. 13,19 In all 3 of these cases, additional evidence, including identification of additional patients and functional studies, was necessary to support pathogenicity of the variants. Had we not conducted additional research in these 3 cases, one could presume that the genes would still have been published as cohorts and these families would have received diagnoses following Similarly, the identification of MORC2 in family #23 reported here was the result of a reanalysis of WES data that was several years old (Table 1).…”

Integrative analysis of rare variants and pathway information shows convergent results between immune pathways, drug targets and epilepsy genes

“…We investigated these genes and saw that the significant signal of these 11 genes was from CC data. C5orf42, HSD17B4, PMPCA, SAMD9L, SCYL1 and TBCK were also reported in NDD studies [36][37][38][39][40][41] . The Epi K. consortium and Epilepsy Phenome/Genome Project 13 used the same CC data set as our current study and reported 7 significant autosomal genes (DEPDC5, GABRG2, GRIN2A, KCNQ2, LGI1, PCDH19, SCN1A); all seven had gTADA PPmax > 0.9, and 6/7 (except GRIN2A) had PPmax > 0.95.…”

Emerging Role of the Autophagy/Lysosomal Degradative Pathway in Neurodevelopmental Disorders With Epilepsy

“…Mutations in TBCK cause a neurodevelopmental syndrome with intellectual disability, coarse face, congenital hypotonia, leukoencephalopathy, progressive motor neuronopathy, and seizures (Bhoj et al, 2016;Chong et al, 2016;Ortiz-González et al, 2018). As suggested by bioinformatic analysis, TBCK encodes a putative Rab GTPase-activating protein, although its function remains elusive.…”

“…As suggested by bioinformatic analysis, TBCK encodes a putative Rab GTPase-activating protein, although its function remains elusive. Loss-of-function mutations in TBCK lead to inhibition of mTORC1 and, thus, to uncontrolled autophagy induction in patient-derived fibroblasts (Bhoj et al, 2016;Ortiz-González et al, 2018). In this model, loss of TBCK results in increased number of APs accompanied by an augmented autophagic flux insensitive to pro-autophagic stimuli (Ortiz-González et al, 2018).…”