TUBB3 encodes neuron-specific β-tubulin isotype III which is the most dynamic tubulin within the β-tubulin family (PMID: 20074521). TUBB3 was first reported in relation to tubulopathies in 2008 (Tischfield et al., PMID: 20074521). TUBB3-related tubulinopathy is characterized by malformations of cortical development, axon guidance defects, white matter abnormalities, and/or congenital fibrosis of the extraocular muscles (CFEOM) due to heterozygous de novo or inherited variants with high penetrance. Individuals may present with variable combinations of malformations of cortical development, dysplasia of the basal ganglia, brainstem, and/or cerebellum, CFEOM, additional cranial nerve involvement, Kallmann syndrome, cyclic vomiting, peripheral neuropathy, and/or contractures. Developmental delays, intellectual disability, ocular motor apraxia, and mirror movements are also frequent features.
Multiple missense variants, most of which were de novo, reported in over 20 probands across 12 publications (PMIDs: 20829227, 26639658, 34562182, 20074521, 28503613, 26130693, 28299356, 34863918, 29187032, 34869359, 26739025, 32573066) and one additional proband from the Brain Gene Registry (braingeneregistry.wustl.edu; ClinVar ID: SCV002103326.1) are included in this curation.
This gene-disease relationship is also supported by experimental evidence. TUBB3 is within the β-tubulin family with the genes TUBB2A and TUBB2B which have been definitively implicated in conditions (tubulinopathy and complex cortical dysplasia with other brain malformations, respectively) with overlapping phenotypes (PMID: 35915025). Additionally, a R262C knock-in mouse model showed defects in the guidance of axons throughout the brain and a thinning of the anterior commissure similar to human patients (PMID: 20074521). Lastly, cells with the variants R262C, A302T, R62Q, and R380C demonstrated increases in microtubule stabilization and increased time in “paused” states compared to wild-type (PMID: 20074521). The mechanism of pathogenicity appears to be gain-of-function (PMID: 20074521).
In summary, there is definitive evidence supporting the relationship between TUBB3 and autosomal dominant TUBB3-related tubulinopathy. 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/Autism GCEP on September 8, 2022 (SOP 9).
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