Multiple and novel molecular mechanisms in TUBA1A-related tubulinopathy: insights from deep clinical and neuroradiological phenotyping.

Purpose Heterozygous TUBA1A variants are a well-recognised cause of malformations of cortical development (MCDs). Although existing literature − predominantly radiologically ascertained cohorts − suggests complete penetrance of the MCD phenotype in this condition, there is also anecdotal contrary evidence. Understanding the clinical spectrum of TUBA1A-related disorders informs counselling and clinical decisions, especially for those identified early in life. Methods Individuals with TUBA1A variants were identified through a large exome sequencing project (DDD project) and analogous studies. Additional clinical data and independent review of the neuroradiology were obtained. Functional studies of the incorporation, reincorporation and depolymerisation of variant tubulin molecules, were performed by expressing wild-type and variant TUBA1A in HEK293 cells. Results We identified 23 individuals with 20 pathogenic/likely pathogenic TUBA1A variants (10 novel). Nearly all had characteristic neuroradiological features of tubulinopathies, but only 25% had MCDs (vs. 99% in previous studies). The variants identified in this study are distinct from those previously described, potentially highlighting a genotype-phenotype relationship, and have a variety of effects on microtubule formation, including reduced depolymerisation that has not been previously observed in TUBA1A-related tubulinopathies. Conclusion Our findings support a lower penetrance of MCDs in TUBA1A-related tubulinopathy, with immediate relevance to variant interpretation and genetic counselling for this condition.