TBCD was first reported in relation to early-onset neurodegenerative encephalopathy in 2016 (Miyake et al., PMID: 27666374). The clinical presentation includes intellectual disability with developmental regression, seizures, hypotonia, spasticity, and secondary microcephaly; brain imaging shows cerebral and cerebellar atrophy, thin corpus callosum, and secondary hypomyelination. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability, therefore, the following disease entities have been lumped into one disease entity: early onset progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT) (OMIM:617193), early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (http://purl.obolibrary.org/obo/MONDO_0044646, ORPHA:496641). Twenty different variants (15 missense, 2 nonsense, 3 splice-disrupting) that have been reported in 15 probands in 6 publications (PMIDs: 27666374, 27666370, 28158450, 27807845, 29921875, 34423067) are included in this curation. More evidence is available in the literature (PMIDs: 27928163, 31240573, 31569255, 34943336, 36527993) but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by experimental evidence including functional assays demonstrating co-immunoprecipitation with TBCE, ARL2, and beta tubulin (PMID 27666374), expression evidence demonstrating decreased levels of TBCD in fibroblasts of affected individuals (PMID 27666370), functional assays demonstrating perturbations in cell proliferation and migration in mouse brain lysates with shRNA-mediated suppression of TBCD (PMID 28158450) and a morpholino-mediated TBCD knockdown in zebrafish that recapitulated some pathological features of the human disease (PMID 27807845). In summary, TBCD is definitively associated with autosomal recessive TBCD-related early-onset neurodegenerative encephalopathy. 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 Brain Malformations gene curation expert panel on 13Mar2025.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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