Submission Details

TUBA8 was first reported in relation to autosomal recessive Polymicrogyria with Optic Nerve Hypoplasia (PMGOH) in 2009 by Abdollahi et al. (PMID: 19896110). This condition is a highly uncommon disease with features of central nervous system anomalies associated with profound developmental delay, low muscle tone in infancy, seizures, and optic nerve hypoplasia. It is also associated with brain structural anomalies like extensive bilateral polymicrogyria and dysplastic or lack of corpus callosum. Three variants (frameshift, missense) that have been reported in 5 probands in 2 publications (PMIDs: 19896110, 29588952) are included in this curation. None of the variants were scored. The frameshift variant, truncating protein in exon 3 and associated with nonsense mediated decay, was found in a homozygous state in two consanguineous Pakistani families, not known to be related. The probands were found by Diggle et al., 2017 (PMID: 28388629) to also harbor a homozygous frameshift variant in SNAP29, which is associated with autosomal recessive CEDNIK Syndrome, a condition that has features of microcephaly with facial anomalies including elongation of the face, upward-slanting palpebral fissures, and mild hypertelorism. Additionally, in the Diggle et al., 2017 article, mice with a homozygous loss of function variant (associated with exon 3 skipping and nonsense mediated decay) did not have polymicrogyria. Another proband, who had compound heterozygous missense variants in trans in TUBA8, had epilepsy but no brain structural anomalies or optic nerve hypoplasia (Fung et al., 2017; PMID: 29588952). Mouse expression-level evidence, by Diggle et al., 2017, was not scored, because there were not significant differences in expression of TUBA8 within the brain between the homozygous mutant and wild-type mice. There is no other expression level evidence available. In summary, the evidence supporting the relationship between TUBA8 and autosomal recessive PMGOH has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role TUBA8 plays in this disease. This classification was approved by the ClinGen Brain Malformations GCEP on the meeting date October 10th, 2023 (SOP Version # 9).