TBR1 gene defects and their possible role for cortical malformations

Abstract

Objective: Many forms of cortical malformation are supposed to be due to a genetic defect. However, except for the group of lissencephalies there is only little knowledge about causative genes for the wide group of cortical development disorders. We present a case with bifrontal pachygyria/polymicrogria who was referred to us because of an abnormal movement pattern and irritability and in whom whole exome sequencing (WES) revealed a mutation in the TBR1 gene. We discuss here its causal role. Methods and results: The initial clinical neurological examination showed an abnormal movement pattern with uncoordinated and uncontrolled movements and irritability. Follow-up until the age of 1 ½ years showed developmental progress with mild delay of motor and cognitive functions and amelioration of neurological signs. Cerebral MRI at 3 months displayed polymicrogyria/ pachygyria involving both frontal lobes. EEG on follow-up demonstrated bifrontal epileptic discharges without clear evidence for clinical seizures. Neither the analysis of the GPR56 gene known to be associated with bifronto-parietal polymicrogyria nor next generation sequencing analyzing a specific gene panel for brain development disorders found a causative mutation. WES finally revealed a de novo frameshift mutation in the TBR1 gene. Conclusion: In the mouse, the TBR1 gene, supposed to be a brain specific transcriptional regulator, is mainly expressed in the telencephalon (Bulfone et al. 1995) and knock out mice present with defects of cortical neuronal migration (Huang et al. 2014). Up to now, defects in the human have only been associated with autism spectrum disorders (Deriziotis et al. 2014). Our case for the first time indicates that its defects may be responsible for cortical maldevelopment in the human, supporting the hypothesis for a leading role of TBR1 in neuronal development based on findings in TBR1 deficient mice. We suggest the inclusion of TBR1 into the genetic analysis of the polymicrogyrias.