Pathogenic variants in TUBB4A are not found in primary dystonia

Abstract

Objective: To determine the contribution of TUBB4A, recently associated with DYT4 dystonia in a pedigree with "whispering dysphonia" from Norfolk, United Kingdom, to the etiopathogenesis of primary dystonia.

Methods: High-resolution melting and Sanger sequencing were used to inspect the entire coding region of TUBB4A in 575 subjects with primary laryngeal, segmental, or generalized dystonia.

Results: No pathogenic variants, including the exon 1 variant (c.4C>G) identified in the DYT4 whispering dysphonia kindred, were found in this study.

Conclusion: The c.4C>G DYT4 mutation appears to be private, and clinical testing for TUBB4A mutations is not justified in spasmodic dysphonia or other forms of primary dystonia. Moreover, given its allelic association with leukoencephalopathy hypomyelination with atrophy of basal ganglia and cerebellum and protean clinical manifestations (chorea, ataxia, dysarthria, intellectual disability, dysmorphic facial features, and psychiatric disorders), DYT4 should not be categorized as a primary dystonia.