The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy

Journal article

Publication Details

Author(s): Hebebrand M, Hüffmeier U, Trollmann R, Hehr U, Uebe S, Ekici AB, Kraus C, Krumbiegel M, Reis A, Thiel C, Popp B
Journal: Orphanet Journal of Rare Diseases
Publication year: 2019
Volume: 14
ISSN: 1750-1172


BackgroundThe TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.ResultsIn three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G>A, p.(Gly436Asp) variant was novel, the two variants c.518C>T, p.(Pro173Leu) and c.641G>A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (agyria-pachygyria) (70%), although reporting was incomplete in the different studies. We identified a total of 121 specific variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein model, 38.6% of all disease-causing variants including those in the C-terminal region are predicted to affect the binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication.ConclusionsWith 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.

FAU Authors / FAU Editors

Ekici, Arif Bülent Dr. rer. nat.
Humangenetisches Institut
Popp, Bernt Dr. med.
Humangenetisches Institut
Thiel, Christian PD Dr.
Medizinische Fakultät
Trollmann, Regina Prof. Dr.
Professur für Kinder- u. Jugendmedizin Schwerpunkt Neuropädiatrie
Uebe, Steffen Dr. rer. nat.
Humangenetisches Institut

External institutions with authors

Universität Regensburg

How to cite

Hebebrand, M., Hüffmeier, U., Trollmann, R., Hehr, U., Uebe, S., Ekici, A.B.,... Popp, B. (2019). The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy. Orphanet Journal of Rare Diseases, 14.

Hebebrand, Moritz, et al. "The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy." Orphanet Journal of Rare Diseases 14 (2019).


Last updated on 2019-18-07 at 07:33