Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions

Signature Genomic Laboratories, PerkinElmer Inc., Spokane, Wash., USA.
Molecular syndromology 09/2012; 3(3):102-112. DOI: 10.1159/000342008
Source: PubMed


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.

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    • "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. "
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    ABSTRACT: Interstitial deletion of 2q24.2 is a rarely described cytogenetic aberration in patients with intellectual disability (ID). Previously reported genotype-phenotype correlation identified a minimum deleted region of 2.65 Mb including 15 genes. Recently, a patient with a de novo 2q24.2 microdeletion of 0.4 Mb encompassing only three genes was described. However, the precise relationship between most deleted genes and the clinical features remains unclear. Here we describe a 12-year-old male patient diagnosed with growth retardation and ID. He also showed microcephaly, right palpebral ptosis, scapular winging, and pectus excavatum. Single nucleotide polymorphisms (SNP) array analysis showed a de novo interstitial deletion of 0.122 Mb at 2q24.2 region harboring only TBR1 (T-box, brain, 1; OMIM: 604616), which encodes a T-box family transcription factor expressed in post-mitotic projection neurons and functionally significant in embryologic corticogenesis. This is the first case of a deletion at 2q24.2 involving only TBR1. This finding narrows the smallest region of overlap (SRO) for deletions in this region and strengthens the previously suggested hypothesis that this gene is a strong candidate for the ID phenotype. The identification of TBR1 as candidate for ID encourages further molecular studies to identify novel mutations to understand the pathogenic effects of its haploinsufficiency. Finally, this report provides a review on 10 2q24.2 microdeletion patients. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Mar 2014 · American Journal of Medical Genetics Part A
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    • "T-Box Traylor et al. (2012) Magri et al. (2011) Krepischi et al. (2010) CNVs (loss) "
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    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.
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    ABSTRACT: The neurons in the olfactory bulb originate from molecularly defined and spatially distinct proliferative regions. Glutamatergic projection neurons are generated during the embryonic period in the local ventricular zone of the olfactory bulb, a territory in the dorsal telencephalon in which the transcription factor Pax6 is expressed. Some cells in this zone also express Tbr1, a marker of glutamatergic neurons. By contrast, embryonic olfactory bulb interneurons are derived from Gsx2 expressing cells in the dorsal lateral ganglionic eminence of the ventral telencephalon, and from progenitors outside the dorsal lateral ganglionic eminence, including the olfactory bulb neuroepithelium. Postnatally, interneurons arise from the subventricular zone of the lateral ventricle, although the rostral migratory stream and the olfactory bulb also appear to serve as a source of neurons. Transcription factors are crucial to generate all classes of neurons and glia in the olfactory bulb, both during development and adulthood. In this article, we discuss and propose models on how the spatial and temporal regulation of transcription factor expression controls the self-renewal, proliferation and cell fate of neural stem cells and progenitors, which finally leads to the generation of distinct functional subtypes of neurons in the developing and adult olfactory bulb. Anat Rec, 2013. © 2013 Wiley Periodicals, Inc.
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