Vegas Nancy, Cavallin Mara, Kleefstra Tjitske, de Boer Lonneke, Philbert Marion, Maillard Camille, Boddaert Nathalie, Munnich Arnold, Hubert Laurence, Bery Amandine, Besmond Claude, Bahi-Buisson Nadia
Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163, Imagine Institute, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Neurology, APHP- Necker Enfants Malades University Hospital, Paris, France.
Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
Eur J Med Genet. 2018 Dec;61(12):759-764. doi: 10.1016/j.ejmg.2018.09.012. Epub 2018 Sep 27.
The advent of next generation sequencing has improved gene discovery in neurodevelopmental disorders. A greater understanding of the genetic basis of these disorders has expanded the spectrum of pathogenic genes, thus enhancing diagnosis and therapeutic management. Genetic overlap between distinct neurodevelopmental disorders has also been revealed, which can make determining a strict genotype-phenotype correlation more difficult. Intellectual disability and cortical malformations are two neurodevelopmental disorders particularly confronted by this difficulty. Indeed, for a given pathogenic gene, intellectual disability can be associated, or not, with cortical malformations. Here, we report for the first time, two individuals with the same de novo mutation in TBR1, leading to a frameshift starting at codon Thr532, and resulting in a premature stop codon 143 amino acids downstream (c.1588_1594dup, p.(Thr532Argfs*144)). These individuals presented with a developmental encephalopathy characterized by frontal pachygyria and severe intellectual disability. Remarkably, 11 TBR1 gene mutations were previously reported in intellectual disability and autism spectrum disorders. Our study supports the observation that TBR1-related disorders range from intellectual disability to frontal pachygyria. We also highlight the need for first-line, good quality neuroimaging for patients with intellectual disability.
新一代测序技术的出现改善了神经发育障碍中的基因发现。对这些疾病遗传基础的更深入了解扩大了致病基因的范围，从而加强了诊断和治疗管理。不同神经发育障碍之间的遗传重叠也已被揭示，这可能使确定严格的基因型-表型相关性更加困难。智力残疾和皮质畸形是特别面临这一困难的两种神经发育障碍。事实上，对于给定的致病基因，智力残疾可能与皮质畸形有关，也可能无关。在此，我们首次报告了两名TBR1基因发生相同新发突变的个体，该突变导致从密码子Thr532开始发生移码，并在下游143个氨基酸处产生一个提前终止密码子（c.1588_1594dup，p.(Thr532Argfs*144)）。这些个体表现为以额部巨脑回和严重智力残疾为特征的发育性脑病。值得注意的是，先前在智力残疾和自闭症谱系障碍中报告了11种TBR1基因突变。我们的研究支持了这样的观察结果，即与TBR1相关的疾病范围从智力残疾到额部巨脑回。我们还强调了对智力残疾患者进行一线高质量神经影像学检查的必要性。
