ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000019.9) (NC_000019.10)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Variants in TUBB4A have been associated with autosomal dominant torsion dystonia 4 (OMIM:128101) and hypomyelinating leukodystrophy 6 (OMIM: 612438). Hamilton et al. 2014 (PMID:24785942) remark that, thus far, only heterozygous missense variants have been reported in TUBB4A, and hypothesize that TUBB4A-associated conditions are caused by "dominant negative, toxic effects." They also postulate that TUBB4A-associated disorders represent "a continuum with the two known phenotypes (autosomal dominant torsion dystonia 4 and hypomyelinating leukodystrophy 6) as extremes," with the only shared features being "the occurrence of extrapyramidal signs." Since the mechanism by which TUBB4A variants result in human disease is not yet understood, the haploinsufficiency and triplosensitivity scores for this gene will remain a 0 at this time. In regards to autosomal dominant torsion dystonia 4 (DYT4): Lohmann et al. (2013)(PMID:23595291) describe a missense variant (Arg2Gly) in the N-terminal autoregulatory domain segregating with disease in a multi-generational Australian family with "whispering dystonia" found by genome sequencing after linkage implicated a 23cM region on 19p13.3-p13.2. Another variant, a missense variant in DOT1L, was also detected in the 9 affected individuals tested. This variant was dismissed as potentially causative by the authors because it was also detected in several unaffected family members that had passed the latest observed age of onset of DYT4, and variants in DOT1L are observed at much higher frequencies in control populations than variants in TUBB4A. mRNA analysis revealed decreased mutant RNA levels using 2 different methods in 3 different cell types. No additional functional studies were performed. Subsequent TUBB4A sequencing in 394 unrelated dystonia patients identified another missense TUBB4A variant in a 71-year-old affected female, whose reportedly affected mother was deceased and unavailable for segregation analysis. Additional reports of missense variants in patients with the above phenotypes include: PMIDs 25168210, 25085639, 24974158, 24850488, 24742798, 24706558, 24526230, 23582646, 23424103.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity