TBR1 encodes a transcription factor with critical roles in corticogenesis, including cortical neuron migration and axon pathfinding, establishment of regional and laminar identity of cortical neurons, and control of glutamatergic neuronal cell fate. Based upon TBR1's role in cortical development, we sought to investigate TBR1 hemizygosity in individuals referred for genetic evaluation of intellectual disability and developmental delay. We describe 4 patients with microdeletions identified by molecular cytogenetic techniques, encompassing TBR1 and spanning 2q24.1q31.1, ranging in size from 2.17 to 12.34 Mb. Only the patient with the largest deletion had a possible cortical malformation. Mild ventriculomegaly is the only common brain anomaly, present in all patients; a Chiari I malformation is seen in 2 patients, and mega cisterna magna is seen in a third. Our findings are consistent with Tbr1 mouse models showing that hemizygosity of the gene requires additional genetic factors for the manifestation of severe structural brain malformations. Other syndromic features are present in these patients, including autism spectrum disorders, ocular colobomas, and craniosynostosis, features that are likely affected by the deletion of genes other than TBR1.
"In recent years, nine comparable submicroscopic deletions within 2q24.2 have been described in patients with a variable clinical phenotype including intellectual disability (ID), short stature, microcephaly, and dysmorphic features, suggesting that haploinsufficiency of one or more genes in 2q24.2 might be responsible for the common phenotypic features in these patients [Krepischi et al., 2010; Takatsuki et al., 2010; Magri et al., 2011; Traylor et al., 2012]. In particular, we described [Palumbo et al., 2012b] a girl with ID and generalized hypotonia carrying a 7.5-Mb deletion in 2q24.1q24.2. "
[Show abstract][Hide abstract] ABSTRACT: Autism spectrum disorders (ASDs) impair social cognition and communication, key higher-order functions centered in the human neocortex. The assembly of neocortical circuitry is a precisely regulated developmental process susceptible to genetic alterations that can ultimately affect cognitive abilities. Because ASD is an early onset neurodevelopmental disorder that disrupts functions executed by the neocortex, miswiring of neocortical circuits has been hypothesized to be an underlying mechanism of ASD. This possibility is supported by emerging genetic findings and data from imaging studies. Recent research on neocortical development has identified transcription factors as key determinants of neocortical circuit assembly, mediating diverse processes including neuronal specification, migration, and wiring. Many of these TFs (TBR1, SOX5, FEZF2, and SATB2) have been implicated in ASD. Here, I will discuss the functional roles of these transcriptional programs in neocortical circuit development and their neurobiological implications for the emerging etiology of ASD.
International Review of Neurobiology 12/2013; 113:167-205. DOI:10.1016/B978-0-12-418700-9.00006-X · 1.92 Impact Factor
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