Objective: The aim of this study is to investigate TUBB4A variants in patients with idiopathic dystonia.

Background: Mutations in TUBB4A, which encodes beta-tubulin 4A, were identified in patients with whispering dysphonia in an Australian family and extended members in Britain, who carried the same variant (Arg2Gly). The phenotype is characterized by marked spasmodic dysphonia and generalized dystonia in most patients. A second de novo variant (Ala271Thr) has been identified in an unrelated patient. To confirm the role of TUBB4A as a dystonia causing gene, it is important to identify other families where putative pathogenic variants segregate with dystonia.

Methods: One hundred and eighty-seven unrelated patients with idiopathic dystonia were screened by amplicon-based targeted sequencing in blood DNA through a customized panel containing 13 dystonia genes, including TUBB4A, in the MiSeq Sequencing System.Variants were validated by Sanger sequencing, pathogenicity prediction were analyzed by in silico algorithms, and their frequency was obtained from a public database of 63000 exomes (ExAc).

Results: We identified two heterozygous missense variants in TUBB4A (NM_006087): c.G137T (p.R46M) and c.G883A (p.D295N). The first variant was identified in two siblings with a positive family history, and onset of symptoms at the ages of 21 and 30 years. One patient had spasmodic dysphonia followed by limb dystonia and generalization after one year; the other had limb dystonia followed by spasmodic dysphonia and cervical involvement three years after onset. One of them described a partial relief of voice symptoms with alcohol. The second variant was identified in 30-year-old male, with onset of dystonia in the upper limb at the age of 6, followed by generalization with marked larynx involvement. As parents were not available, we could not confirm if this was a de novo variant. Both variants are not in the ExAC database. They are highly conserved, located in important functional domains, and are predicted to be detrimental by in silico analysis.

Conclusions: To our knowledge, this is the third independent report of TUBB4A variants associated with dystonia. All cases had marked spasmodic dysphonia, which is one of the main features of the TUBB4A phenotype. Functional studies are warranted to verify their pathogenicity, specially for variants identified in singleton cases.

Acknowledgement: FAPESP grants 2014/17128-2 and 2016/17211-2

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-tubb4a-variants-in-idiopathic-dystonia/