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. 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. 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)). 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.

中文翻译：

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在无智力障碍的自闭症患者中发现了 TBR1 的从头移码致病性变异。


为了能够为自闭症谱系障碍 (ASD) 患者提供准确的遗传咨询，确定异质表型和遗传改变之间的相关性至关重要。在 ASD 中报告的数百个从头致病性变异中，TBR1 中报告了单核苷酸变异和小插入/缺失。该基因编码在大脑发育中发挥关键作用的转录因子。 TBR1 的致病变异通常与严重的 ASD 相关，包括智力障碍和语言障碍。被诊断患有自闭症谱系障碍但没有智力障碍（根据 DSM-IV 诊断为阿斯伯格综合症）的成年人参加了遗传咨询，其中包括代谢评估、分子核型以及与智力障碍、自闭症谱系障碍和智力障碍有关的 268 个基因的筛查。癫痫。此外，这里报告的患者还接受了神经心理学评估、结构磁共振成像和磁共振波谱测量。在此，我们报告一名年轻成年男性的病例，该男性患有典型的自闭症谱系障碍。重要的是，该患者没有表现出智力障碍或语言障碍，尽管 TBR1 中存在从头杂合移码致病性变异，导致早期提前终止密码子 (c.26del, p.(Pro9Leufs*12))。基于此病例报告，我们讨论了 TBR1 在一般大脑发育、语言发育、智力障碍和自闭症谱系障碍 (ASD) 的其他症状中的作用。提供具有此类致病变异的个体的详细临床描述应有助于理解自闭症谱系障碍的基因型-表型关系。