Defining the phenotypical spectrum associated with variants in TUBB2A
Authors: Romina Romaniello
Alma Kuechler
Richard J Leventer
Ute Hehr
Sietske Vermaning
William B Dobyns
Grazia Maria Simonetta Mancini
Dagmar Wieczorek
Luc R√©gal
Nadia Bahi-Buisson
Kathelijn Keymolen
Karin Schaeferhoff
Richard Webster
Tim Vanderhasselt
Katrien Stouffs
Tim Matthias Storm
Tobias B Haack
Marije Meuwissen
Shekeeb Mohammad
Rachel Schot
Ghayda Mirzaa
Anna C Jansen
Stefanie Brock
Esmee Kasteleijn
Ingeborg Kr√§geloh-Mann
Journal: Journal of Medical Genetics (2020)
Discipline: CLINICAL MEDICINE
Keywords: clinical genetics; epilepsy and seizures; genetics; neurology; neurosciences.
Affiliations: Department of Pathology, Universitair Ziekenhuis Brussel, Brussels, Belgium ., Neurogenetics Research Group, Reproduction Genetics and Regenerative Medicine Research Cluster, Vrije Universiteit Brussel, Brussels, Belgium., Department of Radiology, Universitair Ziekenhuis Brussel, Brussels, Belgium., Belgium Center for Reproduction and Genetics, Universitair Ziekenhuis Brussel, Brussels, Belgium., Pediatric Neurology Unit, Department of Pediatrics, Universitair Ziekenhuis, Brussels, Belgium., Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea, Lecco, Italy., Institut fuer Humangenetik, Universitaetsklininikum Essen, Essen, Germany., Institute of Human Genetics, Heinrich Heine University D√ºsseldorf, Dusseldorf, Nordrhein-Westfalen, Germany., Institut f√ºr Humangenetik, Technische Universit√§t M√ºnchen, Munchen, Bayern, Germany., Institute of Medical Genetics and Applied Genomics, University of T√ºbingen, T√ºbingen, Baden-W√ºrttemberg, Germany., Zentrum f√ºr Humangenetik Regensburg, Universit√§tsklinikum Regensburg, Regensburg, Bayern, Germany., Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital T√ºbingen, University of T√ºbingen, T√ºbingen, Germany., Institute of Medical Genetics and Applied Genomics, Eberhard-Karls-Universitat Tubingen Medizinische Fakultat, T√ºbingen, Baden-W√ºrttemberg, Germany., Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands., ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands., Department of Neurology, Children's Hospital at Westmead, Westmead, New South Wales, Australia., Department of Neurology, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia., Division of Genetic Medicine, Department of Pediatrics, Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA., Embryology and Genetics of Congenital Malformations, INSERM, Paris, √éle-de-France, France., Center of Human Genetics, Universiteit Antwerpen, Antwerpen, Belgium., Pediatric Neurology Unit, Universitair Ziekenhuis Brussel, Brussels, Belgium., Center for Medical Genetics, Universitair Ziekenhuis Brussel, Brussels, Belgium, Brussels, Belgium.

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. 

Retracted: No

PubPeer comments:
 Several problems in neuroradiological analyses - First the so-called dysmorphic corpus callosum  Patient 2: are the authors sure that this corpus callosum is dysmorphic? What part is dysmorphic?  Patient 4: the corpus callsoum is considered as mildly dysmorphic. Why? , 
 Second is the problem of partial agenesis  Patient 3: - Legend of the figure: dysmorphic corpus callosum - Table 1: partial agenesis What is the correct diagnosis? The quality of MRI shown on figure is too poor to be correctly analyzed.  Patient 6: Arrowhead is supposed to point partial agenesis of the corpus callosum. Unfortunately, the section is not medio-sagittal and the corpus callosum is difficult to analyze on this figure. Perhaps the authors can share a better section? , 
 The third problem with corpus callosum is hypoplasia Patient 5:  Patient 7:  In these two cases, global reduction of white matter is observed. thus, corpus callosum hypoplasia is due to this global reduction and is not a specific lesion of the corpus callosum. Patient 8:  Are the authors sure that this corpus callosum is reduced according to the standards? , 
 Concerning basal ganglia, table 1 lists several  malformations - Patient 3: dysplasia (MRI performed at 2 months of age) - Patient 6: dysmorphic (the age at which MRI was performed is not available!) - Patient 7: dysmorphic (MRI performed at 10 months of age) - Patient 9: mildly dysmoprhic (but the MRI was not available for review) I would like to know the difference and the definition of dysplasia and dysmorphy. Patient 3:  I guess this is a T2-weighted sequence (it is quite surprising that the authors did not mention it). At this age, How can you distinguish a delay of myelinization and an absence of axons in the internal capsule? How can the authors be sure than basal ganglia are dysplastic (i.e. malformed)? Patient 6:  This is also a T2-weighted sequence. With these artefacts on basal ganglia, how is it possible to conclude? Patient 7:  This is also a T2-weighted sequence. It seems that the anterior arm of the internal capsule is hypoplastic. Why concluding that basal ganglia are dysmorphic? , 
 Another matter of concern  Patient 4 described with prominent Virchow-Robin spaces. I am not convinced  Lateral ventricles of patient 2 are considered as normal whereas those of patients 3 and 4 are enlarged. Why?  What is the difference between enlarged and dilated? ,