Tubulinopathy Case Series: Marked Intrafamilial Phenotypic Variability Associated With a Novel Missense TUBB Variant

Due to diverse clinical presentation, tubulinopathy is usually confirmed by genetic analysis. We report a family case series with a novel missense likely pathogenic variant in the TUBB gene. The proband presented with a severe clinical course, including seizures and global developmental delay starting at 6 months of age. The younger sibling was recognized in the neonatal period due to abnormal cranial ultrasound. Both showed similar brain MRI findings: asymmetrical ventriculomegaly, dysmorphic basal ganglia and asymmetric posterior fossa structures. After identification of the TUBB variant in both siblings and a presumably healthy mother, maternal MRI also demonstrated features consistent with tubulinopathy. This family highlights the critical role of neuroimaging in the diagnosis of tubulinopathies, as characteristic MRI findings can guide genetic interpretation and reclassification of variants. MRI findings enabled reclassification of the TUBB missense variant from variant of uncertain significance to likely pathogenic. The variant showed complete penetrance but markedly variable expressivity, contributing to the broad clinical spectrum associated with TUBB-related disorders.