Pathogenic variants in TUBB2A are usually detected by gene panel analysis or whole-exome sequencing in patients with neurodevelopmental delay and/or epilepsy.
All variants reported to date occurred de novo and were heterozygous missense variants. Mosaic mutations or autosomal dominant inheritance through the parents has not been reported.
Recurrent mutations have been reported affecting p.(Val49*), p.(Gly98Arg), p.Ala248Val, p.(Pro357Leu). Genotype/phenotype correlations could not be established, suggesting a role of additional modifiers, such as environmental factors.
Reported variants are spread throughout the TUBB2A gene, but cluster in the GTPase domain and in the two-layer sandwich domain of the TUBB2A protein. Variants cluster at the protein surface with an impact on protein 3D structure and lateral interactions. Functional studies have suggested defects in either protein folding, heterodimer formation or incorporation of TUBB2A into microtubule polymers for p.Ala248Val. This could not be confirmed for the pathogenic variant p.Asp417Asn observed in a patient with a unique phenotype with neurodegeneration and cerebral atrophy, which instead lead to an accumulation of mitotic cells with aberrant spindle observed.
TUBB2A