Defining the phenotypical spectrum associated with variants in .

BACKGROUND

Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in 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.

METHODS

In order to further refine the phenotypical spectrum associated with , clinical and imaging features of 12 patients with pathogenic variants, recruited via the international network of the authors, were reviewed.

RESULTS

We report 12 patients with eight novel and one recurrent variants spread throughout the 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 patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy.

CONCLUSION

The imaging phenotype associated with pathogenic variants in 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.