Hofmeister Wolfgang, Nilsson Daniel, Topa Alexandra, Anderlid Britt-Marie, Darki Fahimeh, Matsson Hans, Tapia Páez Isabel, Klingberg Torkel, Samuelsson Lena, Wirta Valtteri, Vezzi Francesco, Kere Juha, Nordenskjöld Magnus, Syk Lundberg Elisabeth, Lindstrand Anna
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden.
J Med Genet. 2015 Feb;52(2):111-22. doi: 10.1136/jmedgenet-2014-102757. Epub 2014 Dec 3.
Cytogenetically visible chromosomal translocations are highly informative as they can pinpoint strong effect genes even in complex genetic disorders.
Here, we report a mother and daughter, both with borderline intelligence and learning problems within the dyslexia spectrum, and two apparently balanced reciprocal translocations: t(1;8)(p22;q24) and t(5;18)(p15;q11). By low coverage mate-pair whole-genome sequencing, we were able to pinpoint the genomic breakpoints to 2 kb intervals. By direct sequencing, we then located the chromosome 5p breakpoint to intron 9 of CTNND2. An additional case with a 163 kb microdeletion exclusively involving CTNND2 was identified with genome-wide array comparative genomic hybridisation. This microdeletion at 5p15.2 is also present in mosaic state in the patient's mother but absent from the healthy siblings. We then investigated the effect of CTNND2 polymorphisms on normal variability and identified a polymorphism (rs2561622) with significant effect on phonological ability and white matter volume in the left frontal lobe, close to cortical regions previously associated with phonological processing. Finally, given the potential role of CTNND2 in neuron motility, we used morpholino knockdown in zebrafish embryos to assess its effects on neuronal migration in vivo. Analysis of the zebrafish forebrain revealed a subpopulation of neurons misplaced between the diencephalon and telencephalon.
Taken together, our human genetic and in vivo data suggest that defective migration of subpopulations of neuronal cells due to haploinsufficiency of CTNND2 contribute to the cognitive dysfunction in our patients.
细胞遗传学上可见的染色体易位具有很高的信息量，因为它们即使在复杂的遗传疾病中也能精确找到起强烈作用的基因。
在此，我们报告了一位母亲和女儿，她们都有边缘智力以及诵读困难谱系内的学习问题，并且存在两个明显平衡的相互易位：t(1;8)(p22;q24) 和 t(5;18)(p15;q11)。通过低覆盖配对末端全基因组测序，我们能够将基因组断点定位到2 kb区间。然后通过直接测序，我们将5号染色体p断点定位到CTNND2基因的第9内含子。通过全基因组阵列比较基因组杂交鉴定出另外一例仅涉及CTNND2的163 kb微缺失病例。该5p15.2处的微缺失在患者母亲中也呈嵌合状态存在，但在健康的兄弟姐妹中不存在。然后我们研究了CTNND2多态性对正常变异性的影响，并鉴定出一个对语音能力和左额叶白质体积有显著影响的多态性（rs2561622），该区域靠近先前与语音处理相关的皮质区域。最后，鉴于CTNND2在神经元运动中的潜在作用，我们在斑马鱼胚胎中使用吗啉代寡核苷酸敲低技术来评估其对体内神经元迁移的影响。对斑马鱼前脑的分析显示，有一群神经元错位于间脑和端脑之间。
综合来看，我们的人类遗传学和体内实验数据表明，由于CTNND2单倍剂量不足导致的神经元细胞亚群迁移缺陷，是造成我们患者认知功能障碍的原因。
