The microtubules are dynamic polymeric structures composed of heterodimers of alpha-tubulins and beta-tubulins, which are continuously incorporated and released. Microtubules play essential roles during brain development, including neurogenesis, neuronal migration, and post-migrational organization. In addition, they participate in mitosis, ciliary/flagellar motility, and intracellular transport.
TUBB2A encodes for beta-tubulin 2A. It was first reported in relation to complex cortical dysplasia with other brain malformations-5 in 2014 (Cushion et al., PMID:24702957). It is characterized by variable neuroimaging abnormalities, including corpus callosum anomalies, enlarged ventricles, dysgyria, dysmorphic basal ganglia, cerebellar vermis hypoplasia or dysplasia, and decreased white matter. Epilepsy, intellectual disability/global developmental delay, speech impairment, and motor impairment are frequent features.
All phenotypes listed above have been grouped as one disease entity: Tubulinopathy (MONDO:0100153).
Evidence supporting this gene-disease relationship includes case-level data only. Summary of Case Level Data: 11.5 POINTS. This curation has 14 missense variants in 20 probands in 6 publications (PMID: 24702957, 28840640, 29547997, 32203252, 33776625, 33776625). 4 probands with the variant p.Ala248Val were not scored due to relatively high allele frequency and reports of VUS and likely benign cases in Clinvar.
In summary, there is DEFINITIVE evidence to support this gene-disease relationship. No convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on 01/05/2023 (SOP Version 9)
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