TUBA4A

Inheritance Pattern: AD

Disease ID:MONDO:0979231

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0979231

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014531

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0979230

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0019952

Submitter: PanelApp Australia

Inheritance Pattern: Unknown

Disease ID:MONDO:0014531

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014531

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014531

Submitter: ClinGen

TUBA4A was first reported in relation to autosomal dominant amyotrophic lateral sclerosis 22 (ALS) in 2014 (Smith BN, et al., 2014, PMID: 25374358). TUBA4A encodes an α-tubulin subunit, which together with β-tubulin constitutes the tubulin heterodimer, the building block of microtubules. ALS-associated TUBA4A variants are suggested to dysregulate neuronal function by disruption of microtubule dynamics and stability. ALS is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 14 variants have been reported in relation to ALS (mostly missense, as well as one nonsense, one splice site, and one frameshift). Variants in this gene have been reported in at least 14 probands in 4 publications (PMIDs: 25374358, 25893256, 28069311, and 295405137). Experimentally, this gene-disease relationship is supported by its role as a constituent of cytoskeleton (PMID: 25374358), expression in the nervous system (PMID: 25374358, PMID: 30030593), and a zebrafish model with overlapping phenotypes though mechanism may differ from that proposed in patients (PMID: 38463699). TUBA4A mutants appear to disrupt microtubule dynamics and stability through a dominant-negative mechanism, however there is an absence of functional data from primary tissue of TUBA4A mutation carriers. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was previously approved by the ClinGen ALS GCEP on 09/14/2021, it was recurated on 03/27/2025 and a new zebrafish model (PMID: 38463699) was identified but there was no change of classification.

Inheritance Pattern: AD

Disease ID:MONDO:0015372

Submitter: ClinGen

*TUBA4A* was first reported in relation to autosomal dominant macrothrombocytopenia in 2019 (Strassel et al., 2019, PMID: 30760556). *TUBA4A* encodes an α-tubulin subunit, which together with β-tubulin constitutes the tubulin heterodimer, the building block of microtubules and it is well established that microtubules are key actors in the formation of proplatelets from mature megakaryocytes (Reviewed in PMID: 31315202). Evidence supporting this gene-disease relationship includes case-level data and experimental data. One macrothrombocytopenia patient has been reported with two rare *TUBA4A* missense variants in cis (PMID: 30760556). No functional evidence is yet available to support one, or both, variants as deleterious. This gene-disease relationship is supported by its shared function with *TUBB1* as a building block of microtubules. *TUBA4A* has a high level of microtubule incorporation (PMID: 25374358) and expression of *TUBA4A* is particularly enriched in platelet microtubules (PMID: 30760556). Additionally, mice carrying a missense mutation in the Tuba4a gene, displayed macrothrombocytopenia and structural abnormalities in the marginal band of platelets, similar to the patient. In summary, there is very limited genetic evidence and more evidence is needed to support a causal role, however no convincing evidence has emerged that contradicts the gene-disease relationship. Two additional macrothrombocytopenia families have been identified with *TUBA4A* variants but are not reported in a peer reviewed article or ClinVar submission. These families were presented at the ISTH 2024 Congress (https://isth2024.eventscribe.net/fsPopup.asp?efp=R0tKSkNBT0ExNjMzNg&PresentationID=1433440&mode=presInfo). Five macrothrombocytopenic patients from two unrelated families carrying two heterozygous variants, respectively (p.(Lys430del) in family A and p.(Asp431Tyr) in family B (CATCH study, ClinicalTrials.gov identifier: NCT04272970) were identified by WES. Of note, *TUBA4A* has also been implicated in autosomal dominant amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. and apparently dominant negative *TUBA4A* variants are suggested to dysregulate neuronal function by disruption of microtubule dynamics and stability. Based on differences in phenotype and proposed molecular mechanisms these disease entiteis have been considered seperately and the relationship to ALS was curated by the ALS GCEP. This gene-disease pair was originally evaluated by the HT GCEP on 2021 Jun 23. It was reevaluated on 2023 Nov 06. As a result of this reevaluation no additional patients were scored and the classification remained Limited. Three additional disease assertions have been made in OMIM in relation to *TUBA4A*, Congenital myopathy 26, Oocyte/zygote/embryo maturation arrest 23, and Spastic ataxia 11, autosomal dominant. There is no variant or phenotype overlap with these additional diseases and autosomal dominant macrothrombocytopenia is still considered seperately.

Inheritance Pattern: AD

Disease ID:MONDO:0014531

Submitter: Genomics England PanelApp