Defining the phenotypical spectrum associated with variants in <i>TUBB2A</i>.

Abstract

Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in <i>TUBB2A</i> have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. In order to further refine the phenotypical spectrum associated with <i>TUBB2A</i>, clinical and imaging features of 12 patients with pathogenic <i>TUBB2A</i> variants, recruited via the international network of the authors, were reviewed. We report 12 patients with eight novel and one recurrent variants spread throughout the <i>TUBB2A</i> gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in <i>TUBB2A</i> patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. The imaging phenotype associated with pathogenic variants in <i>TUBB2A</i> is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.