Cortical Dysplasia, Complex, with Other Brain Malformations 4 via the TUBG1 Gene

Cortical dysplasia, complex, with other brain malformations 4 is one type of heterogeneous tubulinopathy and is characterized by posterior predominant pachygyria. The major features include severe microcephaly, severe motor and cognitive impairment, and early onset seizures with generalized tonic-clonic, tonic–atonic–myoclonic, focal, versive and infantile spasms. Cataract and spastic tetraplegia also can be seen in some patients. Brain MRI shows pachygyric cortex with posterior to anterior gradient, enlarged lateral ventricles most pronounced over the posterior horns, and variable degrees of reduced white matter volume (Brock et al. 2018. PubMed ID: 29706637; Poirier et al. 2013. PubMed ID: 23603762). Seizure types are variable and include generalized tonic-clonic, atonic, myoclonic, complex partial, and absence.

Cortical dysplasia, complex, with other brain malformations 4 is inherited in an autosomal dominant manner and is caused by pathogenic variants in the TUBG1 gene. TUBG1 encodes gamma-tubulin which is a structural protein of the centrosome and highly expressed in fetal brain. The TUBG1 protein associates with other proteins to form the gamma tubulin ring complex which plays a role in microtubule nucleation. The tubulin-related cortical dysgeneses are considered to involve a combination of abnormal neuronal proliferation, migration, differentiation and axonal guidance (Poirier et al. 2013. PubMed ID: 23603762). The reported pathogenic variants in TUBG1 include missense variants only at this time. Large deletions or duplications have not been reported (Brock et al. 2018. PubMed ID: 29706637; Poirier et al. 2013. PubMed ID: 23603762; Human Gene Mutation Database). Almost all of the pathogenic variants have occurred de novo. Germline mosaicism has been seen in one patient (Brock et al. 2018. PubMed ID: 29706637).

Tubulinopathies are clinically and genetically heterogeneous. Clinical sensitivity for TUBG1 cannot be estimated because only a small number of patients have been reported. Analytical sensitivity should be high because all pathogenic variants reported are detectable by sequencing.

Our DNA sequencing test involves bidirectional Sanger DNA sequencing of all coding exons of the TUBG1 gene plus ~10 bp of flanking non-coding DNA on either side of each exon. We will also sequence any single exon (Test #100) in family members of patients with a known pathogenic variant or to confirm research results.