The association of TUBB4A variants with autosomal dominant neurological disease first occurred in 2013 with whispering dystonia type 4 (Hersheson et al., PMID: 23424103 and Lohmann et al., PMID: 23595291) and hypomyelination with atrophy of the basal ganglia and cerebellum (Simons et al., PMID: 23582646). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s), inheritance pattern, and found that the spectrum of phenotypic variability could exist between the described disease entities. Therefore, the prior disease entities have been lumped into one disease entity, TUBB4A Related Neurologic Disorder (MONDO: 0800470). Clinical characteristics include a variable age of onset with a spectrum of physical and radiographical findings.
The TUBB4A gene encodes a protein that is a member of the highly conserved β-tubulin protein family that forms heterodimers with α-tubulins and then in turn forms copolymers that assemble into microtubules, an essential component of the cytoskeleton and is primarily expressed in the nervous system. Eleven missense variants reported in fifteen probands across five publications (PMIDs: 25085639, 32943487, 23582646, and 33597727) including one with linkage analysis (PMID: 23595291) are included in this curation. The mechanism of pathogenicity is gain-of-function. Gene-disease relationship is supported by cellular-based expression studies (PMID: 35668344) and animal models including a mouse model (PMID: 32463361). More evidence exists in the literature, but the maximum required score for genetic evidence (12 pts.) has been reached. In summary, definitive evidence supports the relationship between TUBB4A and autosomal dominant TUBB4A Related Neurologic Disorder, with rigorous and reproducible evidence in research and clinical diagnostic settings. This gene-disease curation based on ClinGen criteria was approved by the Leukodystrophy and Leukoencephalopathy GCEP via email communications on March 6, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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