Abstracts

Rationale: Tubulinopathies are disorders of neuronal migration caused by mutations in genes encoding different α-, β-, and γ- tubulin types. Tubulins are the critical proteins that form microtubules, which play a critical role in nervous system development, including cell division of neuronal progenitors and neuronal migration. Mutations in TUBA1A, TUBA8, TUBB2A, TUBB2B, TUBB3, TUBB5, and TUBG1 have been associated with a spectrum of cortical malformations, including agenesis of the corpus callosum and brainstem and cerebellar vermian hypoplasia. In addition to the malformation, the patients have moderate to profound developmental delay (DD)/intellectual disability and epilepsy. Mutations in TUBB2A have only been reported in 4 cases, all of whom had MRI abnormalities and 3 who had epilepsy (Am J Hum Genet 2014;94; 634–641; J Child Neurol 2017; 32;127-131). We report 5 patients with TUBB2A mutations and novel clinical presentations, expanding the phenotypic spectrum associated with mutations in this gene.  Methods: Patients with TUBB2A mutations were identified after undergoing genetic testing via commercially available next-generation sequencing targeted gene panels or exome sequencing. Indication for testing included brain malformation, microcephaly and/or DD. Results: Patient 1 was prenatally diagnosed with ventriculomegaly, hypoplastic brainstem and cerebellum, and thin cortical mantle with lissencephaly. Neonatal seizures were present; the patient died at 6 days of age. Patient 2 was prenatally diagnosed with lissencephaly, thickened cortex, and small cerebellum. Postnatal MRI identified frontal polymicrogyria and thin corpus callosum. At age 3 months, he is severely delayed, but without seizures. Patient 3 is microcephalic with profound global DD and progressive neuromuscular weakness. MRI showed white matter volume loss and thin corpus callosum. She has optic nerve hypoplasia and is tracheostomy dependent due to progressive diaphragmatic weakness. She does not have seizures. Patient 4 is the identical twin of patient 3 and presented with a similar clinical course. She is microcephalic. MRI showed generalized decreased white matter volume with thin corpus callosum. She has not had seizures. Genetic confirmation for the familial TUBB2A variant is in progress. Patient 5 has global DD and ADHD. He is microcephalic, but has not had any seizures and MRI was normal. Conclusions: These 5 patients expand the phenotype associated with TUBB2A mutations to include severe brain malformations diagnosed prenatally, a potentially progressive neuromuscular phenotype, and a milder phenotype with DD, but without epilepsy or brain malformation. Further studies testing the functional effect of these mutations should be performed to better understand the pathophysiology underlying TUBB2A mutations and support the pathogenicity of these variants. Overall, we extend the phenotype of TUBB2A mutations beyond epilepsy and brain malformations which has important genetic counseling implications. This pattern of diverse phenotypes is consistent across all the tubulinopathies. Funding: N/A