Expanding genetic and clinical spectra of β-tubulinopathies: A Korean study

Tubulin proteins form microtubules, which are critical for neuronal cell migration. In humans, there are at least 27 tubulin genes. Pathogenic variants in these genes cause tubulinopathies, which are characterized by diverse neurodevelopmental symptoms and brain malformations. This study analyzed the genetic variants and clinical characteristics of 12 patients (3 males, 9 females) with confirmed β-tubulinopathies. A retrospective chart review indicated that diagnoses were made via exome, genome, or targeted next-generation panel sequencing. Most patients (11/12) showed significant developmental delay and hypotonia. Other neurological symptoms included ocular motility disorders (7/12), ataxia (6/12), seizures (3/12), and microcephaly (2/12). The median age at symptom onset was 10 months (range 0 - 24). Corpus callosum abnormalities were the most common brain malformation, present in 10 patients, including one case of complete agenesis. Basal ganglia abnormalities and cerebellar hypoplasia were each observed in 9 patients. Cortical abnormalities, white matter changes, and brainstem hypoplasia were each present in 8 patients. Severe lissencephaly was not observed. Ten pathogenic or likely pathogenic missense variants were identified in five β-tubulin genes (TUBB2A, TUBB2B, TUBB3, TUBB4A, and TUBB5). Most variants were de novo, but one was a maternally inherited variant, c.211 G > A in TUBB3, which was associated with milder features. A novel variant in TUBB2A, c.1234 G > A p.(Glu412Lys), was also identified. These genetic variations were associated with a broad phenotypic spectrum of β-tubulinopathies, including complex brain malformations and neurodevelopmental disorders. Despite its rarity, tubulinopathy may be considered in the differential diagnosis for patients presenting with developmental delay and brain malformations.