A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability
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A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability Laurie-Anne Sapey-Triomphe1,2, Julie Reversat3, Gaëtan Lesca3,4, Nicolas Chatron3,4, Marina Bussa5,6, Sylvie Mazoyer4, Christina Schmitz1* , Sandrine Sonié1,5,6 and Patrick Edery3,4
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.
Background Autism Spectrum Disorder (ASD) is characterized by difficulties in social interactions and communication, together with restricted repertories of interests and behaviors and an atypical sensory sensitivity [1]. The prevalence of this neurodevelopmental disorder is around 1% [2]. The previous version of the Diagnostic * Correspondence: [email protected] 1 Lyon Neuroscience Research Center, Brain Dynamics and Cognition team, INSERM UMRS 1028, CNRS UMR 5292, Université Claude Bernard Lyon 1, Université de Lyon, F-69000 Lyon, France Full list of author information is available at the end of the article
and Statistical Manual of Mental Disorders (DSM-IV) [3] distinguished subtypes of ASD, whereas the current version (DSM-V) considers autism as a spectrum [1]. This notion of spectrum highlights the diversity of symptoms and severity in ASD (e.g., individuals with or without intellectual disability, verbal or non-verbal). Even though major advances have been done, the g
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