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<p>This study delineated the clinical phenotypes of epilepsy patients harboring <i>TUBB2A</i> 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 <i>TUBB2A</i> variants were evaluated. <i>TUBB2A</i>-FLAG and <i>TUBB2A</i>-EGFP plasmids were constructed to investigate the functional implications of <i>TUBB2A</i> 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 <i>TUBB2A</i> 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 <i>TUBB2A</i>-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 <i>TUBB2A</i> variants that perturb tubulin dimer linkage were observed to have a higher proportion of severe phenotypes, such as pachygyria.</p>

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TUBB2A related epilepsy: novel variants and genotype-phenotype correlation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月24日

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  • Wenwei Liu,
  • Miaomiao Chen,
  • Xiaowei Tang,
  • Ying Zhu,
  • Yufen Li,
  • Ling Liang,
  • Zhongyan Wu,
  • Yuwu Jiang,
  • Yuxin Yin,
  • Fan Mei,
  • Yuehua Zhang

摘要

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.