Defining the phenotypical spectrum associated with variants in TUBB2A

Area of Science:

• Neurogenetics
• Developmental Neuroscience
• Medical Genetics

Background:

• Tubulinopathies are a group of brain malformations caused by variants in tubulin superfamily genes.
• Previous studies reported TUBB2A variants in 10 patients with diverse brain imaging findings, including polymicrogyria and cerebellar atrophy.

Purpose of the Study:

• To further delineate the phenotypic spectrum associated with TUBB2A gene variants.
• To analyze clinical and neuroimaging features in a cohort of patients with pathogenic TUBB2A variants.

Main Methods:

• Review of clinical and imaging data from 12 patients with pathogenic TUBB2A variants.
• Analysis of novel and recurrent variants within the TUBB2A gene.

Main Results:

• Twelve patients identified with eight novel and one recurrent TUBB2A variants.
• High incidence of early-onset seizures (91.7%), intellectual disability, and severe motor delay (36.4% non-ambulatory).
• Variable cerebral cortex presentation: normal in 5/12, dysgyria in 7/12; associated brain malformations were less common than in other tubulinopathies.

Conclusions:

• Pathogenic TUBB2A variants lead to a highly variable imaging phenotype, from normal cortex to severe dysgyria.
• No clear genotype-phenotype correlation was found for recurrent variants, suggesting involvement of other genetic or environmental factors.