Submission Details

TBCK was first reported in relation to autosomal recessive syndromic complex neurodevelopmental disorder in 2016 (Bhoj et al., PMID: 27040691). There is marked clinical variability in patients, ranging from mild to severe. The severe phenotype is progressive, often leads to early death, and consists of prominent motor neuron degeneration, profound intellectual disability, leukoencephalopathy and brain atrophy, chronic respiratory failure, refractory epilepsy, and clinical features reminiscent of lysosomal storage disorders. The milder form is non-progressive, and presents with mild intellectual disability, autistic features, and mild motor impairment. The biological factors underlying this variable disease presentation remain unknown. Seven variants (nonsense, frameshift, and in-frame exonic deletion) reported in six probands from four publications (PMIDs: 27040691, 30591081, 35095425, 36317458) are included in this curation. Three variants are recurrent, including a founder variant known as the Boricua mutation in individuals of Puerto Rican descent (p.Arg126*) that is associated with the severe phenotype (PMIDs: 27040691, 27040692). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss of function (PMIDs: 27040691, 27040692, 34816123, 35095425).

TBCK encodes a putative GTPase-activating protein and has been shown to control cell growth and proliferation, actin cytoskeleton dynamics, and mTOR signaling. This gene-disease relationship is supported by findings in skin, lymphocytic, and neuroprogenitor cells from both mildly and severely affected individuals equally demonstrating reduced mRNA and protein expression and decreased mTOR signaling compared to controls (PMIDs: 27040691, 27040692, 35095425). Greater mitochondrial and lysosomal defects were observed in fibroblasts from individuals expressing the severe neurodegenerative phenotype compared to those with a milder phenotype (PMID: 29283439). Additionally, histopathological features of lysosomal storage disease were detected by autopsy in siblings affected with the more severe TBCK encephalopathy (PMID 34816123).

In summary, there is definitive evidence supporting the relationship between TBCK and autosomal recessive syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 7, 2024 (SOP Version 10).