TUBB2A related epilepsy: novel variants and genotype-phenotype correlation

This study delineated the clinical phenotypes of epilepsy patients harboring TUBB2A variants and explored the pathogenesis of novel variants in HEK293T cells. The clinical data of 5 epilepsy patients in our cohort and 23 epilepsy patients from published studies carrying TUBB2A variants were evaluated. TUBB2A-FLAG and TUBB2A-EGFP plasmids were constructed to investigate the functional implications of TUBB2A variants. In 28 patients with epilepsy, the seizure onset age spanned from neonatal period to 8 years old, with 61% experiencing seizures before 1-year-old. The prevalent seizure types were epileptic spasms (32%) and focal seizures (32%). All 28 patients showed varying degrees of developmental delay, and 93% had malformation of cortical development (MCD). All identified TUBB2A variants were missense variants. Three-dimensional structure predictions revealed that 83% of patients diagnosed with pachygyria possessed variants situated near or at the linkage of α-β tubulin. We investigated 4 novel variants and 4 reported variants and found that all 8 variants affected the morphology of spindle apparatus and dynamics of microtubules. Variants located at or near α-β tubulin dimer interface exerted a pronounced influence on the morphology and dynamic of microtubules. Most patients with TUBB2A-related epilepsy experience seizures before 1-year-old. Over 90% of these patients presented with MCDs, and all displayed varying degrees of developmental delay. Patients with TUBB2A variants that perturb tubulin dimer linkage were observed to have a higher proportion of severe phenotypes, such as pachygyria.