Lissencephaly 3 via the TUBA1A Gene

Lissencephalies and subcortical band heterotopia (SBH) are a group of cerebral malformations involving arrest of neuronal migration during embryogenesis. Lissencephaly is characterized by simplification or absence of the brain convolutions, resulting in a smooth appearance. SBH, also known as double cortex, is characterized by abnormal bands of neurons beneath a normal cortex. Lissencephalies and SBH are characterized by intellectual disability and seizures. Additional features include microcephaly, subtle dysmorphic features, failure to thrive, difficulty feeding and swallowing, malformations of the digits, muscle spasms, myoclonic jerks, cognitive impairment, and poor social interactions (Leventer et al. 2001. PubMed ID: 11502906; Wallerstein et al. 2008. PubMed ID: 18462864; Dobyns. 2010. PubMed ID: 20331703; Di Donato et al. 2017. PubMed ID: 28440899). The incidence of lissencephalies is ~1:100,000 live births (https://www.orpha.net).

Lissencephalies are clinically and genetically heterogeneous. Several forms are recognized. They are distinguished on the basis of the clinical features and the causative genes.

Lissencephaly 3 can be distinguished by MRI findings consistent with a posterior greater than anterior gradient of lissencephaly, abnormalities of the cerebellum, corpus callosum and brainstem, and ventricles enlargement. Additional findings include microcephaly, reduced white matter, and hypoplasia of the brainstem, cerebellum and cerebellar vermis. Neurological symptoms include motor delay, severe intellectual disability, mild to severe cognitive impairment and intractable tonic-clonic seizures (Poirier et al. 2007. PubMed ID: 17584854).

Lissencephaly 3 is caused by heterozygous pathogenic variants in the TUBA1A gene (Keays et al. 2007. PubMed ID: 17218254; Bahi-Buisson et al. 2008. PubMed ID: 18728072). To date, ~30 pathogenic variants have been reported. They are all missense variants (Human Gene Mutation Database). Pathogenic TUBA1A variants have been documented to be de novo in most patients (Bahi-Buisson and Cavallin. 2016. PubMed ID: 27010057). Germline and somatic pathogenic variants have been reported (Zillhardt. 2016. PubMed ID: 26395554; Jansen et al. 2011. PubMed ID: 21403111).

The TUBA1A gene encodes a brain specific tubulin B-alpha-1 (TUBA1A) protein. TUBA1A is predicted to have a role in microtubule function, which is important for neuronal migration during early embryonic development (Kumar et al. 2010. PubMed ID: 20466733).

Pathogenic variants in the TUBA1A gene have been detected in about 5% of patients from a large cohort of children with lissencephaly (Di Donato et al. 2018. PubMed ID: 29671837).

This test provides full coverage of all coding exons of the TUBA1A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).