Year: 2020
Type: article
Study design: Observational Study
Abstract: Background Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. Methods In order to further refine the phenotypical spectrum associated with TUBB2A , clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. Results We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. Conclusion The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype–phenotype correlations could be established, suggesting the role of additional modifiers.
Source: Journal of Medical Genetics
Authors: Stefanie Brock, Tim Vanderhasselt, Sietske Vermaning, Kathelijn Keymolen, Luc Régal, Romina Romaniello, Dagmar Wieczorek, Tim Matthias Storm, Karin Schaeferhoff, Ute Hehr, Alma Kuechler, Ingeborg Krägeloh-Mann, Tobias B Haack, Esmee Kasteleijn, Rachel Schot, Grazia Maria Simonetta Mancini, Richard Webster, Shekeeb Mohammad, Richard J Leventer, Ghayda Mirzaa, William B Dobyns, Nadia Bahi-Buisson, Marije Meuwissen, Anna C Jansen, Katrien Stouffs
Institutions: Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, IRCCS Eugenio Medea, Essen University Hospital, Heinrich Heine University Düsseldorf, Institut für Humangenetik, Technical University of Munich, University of Tübingen, University Hospital Regensburg, University Children's Hospital Tübingen, Erasmus MC, Children's Hospital at Westmead, Murdoch Children's Research Institute, Seattle Children's Research Institute, Inserm, University of Antwerp
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Universitaire Stichting, Australian Government, Fonds Wetenschappelijk Onderzoek, Australian Genomics Health Alliance, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Institute of Neurological Disorders and Stroke, Medical Research Future Fund
OpenAlex ID: W3036688430