Traylor R N, Dobyns W B, Rosenfeld J A, Wheeler P, Spence J E, Bandholz A M, Bawle E V, Carmany E P, Powell C M, Hudson B, Schultz R A, Shaffer L G, Ballif B C
Signature Genomic Laboratories, PerkinElmer Inc., Spokane, Wash., USA.
Mol Syndromol. 2012 Sep;3(3):102-112. doi: 10.1159/000342008. Epub 2012 Aug 23.
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.
TBR1编码一种转录因子，在皮质发生过程中发挥关键作用，包括皮质神经元迁移和轴突寻路、皮质神经元区域和层状身份的确立以及谷氨酸能神经元细胞命运的控制。基于TBR1在皮质发育中的作用，我们试图研究因智力残疾和发育迟缓接受基因评估的个体中的TBR1半合子状态。我们描述了4例通过分子细胞遗传学技术鉴定出微缺失的患者，这些微缺失包含TBR1基因，跨越2q24.1q31.1，大小从2.17到12.34 Mb不等。只有缺失最大的患者可能存在皮质畸形。轻度脑室扩大是所有患者中唯一常见的脑部异常；2例患者出现Chiari I畸形，1例患者出现巨大枕大池。我们的发现与Tbr1小鼠模型一致，表明该基因的半合子状态需要其他遗传因素才能表现出严重的结构性脑畸形。这些患者还存在其他综合征特征，包括自闭症谱系障碍、眼裂、颅缝早闭，这些特征可能受TBR1以外基因缺失的影响。
