Genome-wide sequencing for the identification of rearrangements associated with Tourette syndrome and obsessive-compulsive disorder
Genome-wide sequencing for the identification of rearrangements associated with Tourette syndrome and obsessive-compulsive disorder
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DOI：
10.1186/1471-2350-13-123
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发表时间：
2012-12-19
影响因子：
--
通讯作者：
Feuk, Lars
中科院分区：
文献类型：
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作者：
Hooper, Sean D.;Johansson, Anna C. V.;Feuk, Lars
背景：抽动秽语综合症（TS）是一种儿童神经精神疾病，其特征是运动和语言抽动。尽管已经提出了 TS 病因中的多个基因，但其遗传机制仍知之甚少。方法：利用细胞遗传学和 FISH 分析，我们在一名患有 TS 和强迫症 (OCD) 的男性患者中发现了明显平衡的 t(6,22)(q16.2;p13)。为了绘制断点图谱并识别其他亚显微重排，我们对先证者的 DNA 进行了全基因组配偶对测序和 CGH 阵列分析。结果：序列和 CGH 阵列分析显示位于染色体 6q 断点 1.3 Mb 端粒处的 400 kb 缺失，这在对照中尚未报告。这一缺失影响了三个基因（GPR63、NDUFA4 和 KLHL32），并且与之前在一名患有自闭症和语言迟缓的女孩身上发现的缺失区域重叠。先证者的母亲也是易位携带者，被诊断患有强迫症并分享了该缺失。我们还描述了进一步的潜在相关重排，虽然在智人中未作图谱，但与黑猩猩基因组一致。结论：我们得出结论，分辨率相对较低的全基因组测序可用于鉴定亚显微重排。我们还表明，使用全基因组测序数据的标准分析，大的重排可能会逃脱检测。我们的研究结果进一步提供了染色体 6q16 上 TS 和 OCD 的候选区域。
Background: Tourette Syndrome (TS) is a neuropsychiatric disorder in children characterized by motor and verbal tics. Although several genes have been suggested in the etiology of TS, the genetic mechanisms remain poorly understood.Methods: Using cytogenetics and FISH analysis, we identified an apparently balanced t(6,22)(q16.2;p13) in a male patient with TS and obsessive-compulsive disorder (OCD). In order to map the breakpoints and to identify additional submicroscopic rearrangements, we performed whole genome mate-pair sequencing and CGH-array analysis on DNA from the proband.Results: Sequence and CGH array analysis revealed a 400 kb deletion located 1.3 Mb telomeric of the chromosome 6q breakpoint, which has not been reported in controls. The deletion affects three genes (GPR63, NDUFA4 and KLHL32) and overlaps a region previously found deleted in a girl with autistic features and speech delay. The proband's mother, also a carrier of the translocation, was diagnosed with OCD and shares the deletion. We also describe a further potentially related rearrangement which, while unmapped in Homo sapiens, was consistent with the chimpanzee genome.Conclusions: We conclude that genome-wide sequencing at relatively low resolution can be used for the identification of submicroscopic rearrangements. We also show that large rearrangements may escape detection using standard analysis of whole genome sequencing data. Our findings further provide a candidate region for TS and OCD on chromosome 6q16.