A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability

Abstract

Background In order to be able to provide accurate genetic counseling to patients with Autism Spectrum Disorder (ASD), it is crucial to identify correlations between heterogeneous phenotypes and genetic alterations. Among the hundreds of de novo pathogenic variants reported in ASD, single-nucleotide variations and small insertions/deletions were reported in TBR1. This gene encodes a transcription factor that plays a key role in brain development. Pathogenic variants in TBR1 are often associated with severe forms of ASD, including intellectual disability and language impairment. Methods Adults diagnosed with ASD but without intellectual disability (diagnosis of Asperger syndrome, according to the DSM-IV) took part in a genetic consultation encompassing metabolic assessments, a molecular karyotype and the screening of a panel of 268 genes involved in intellectual disability, ASD and epilepsy. In addition, the patient reported here went through a neuropsychological assessment, structural magnetic resonance imaging and magnetic resonance spectroscopy measurements. Results Here, we report the case of a young adult male who presents with a typical form of ASD. Importantly, this patient presents with no intellectual disability or language impairment, despite a de novo heterozygous frameshift pathogenic variant in TBR1, leading to an early premature termination codon (c.26del, p.(Pro9Leufs*12)). Conclusion Based on this case report, we discuss the role of TBR1 in general brain development, language development, intellectual disability and other symptoms of ASD. Providing a detailed clinical description of the individuals with such pathogenic variants should help to understand the genotype-phenotype relationships in ASD.

Neuroimaging genetics approaches to identify new biomarkers for the early diagnosis of autism spectrum disorder

“…The gene T-brain 1 (TBR1) encodes the transcription factor TBR1, which mediates gene transcription and cortical neurogenesis and is crucial for normal neurodevelopment. Several preclinical and clinical studies have shown TBR1 to be implicated in ASD [57][58][59][60][61]. TBR1 haploinsufficiency results in defective axonal projections of amygdala neurons and impairs social interaction, memory, cognitive flexibility [58], and neuronal activation of the olfactory system in mice models [57].…”

Possible roles of deep cortical neurons and oligodendrocytes in the neural basis of human sociality

“…FOXP2 and TBR1 are the L6 markers. TBR1 is a T-box brain transcription factor that was identified in patients with ASD and ID (Nambot et al 2020 ; Sapey-Triomphe et al 2020 ; Vegas et al 2018 ), has been shown to regulate cortical lamina formation, differentiation of L6, dendritic patterning, and inhibitory synaptic density during development (Co et al 2022 ; Fazel Darbandi et al 2018 ; Bedogni et al 2010 ). Tbr1 haploinsufficiency in mice resulted in axonal projection defects in amygdala neurons and impairments in social interaction, USVs, and cognitive flexibility (Huang et al 2014 ).…”