Clinical and molecular characterization of three genomic rearrangements at chromosome 22q13.3 associated with autism spectrum disorder
Clinical and molecular characterization of three genomic rearrangements at chromosome 22q13.3 associated with autism spectrum disorder
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DOI：
10.1097/ypg.0000000000000151
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发表时间：
2017-02-01
影响因子：
0.9
通讯作者：
Gau, Susan Shur-Fen
中科院分区：
文献类型：
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作者：
Chen, Chia-Hsiang;Chen, Hsin-I;Gau, Susan Shur-Fen
目的染色体22 q13是基因组重排的热点区域，可能导致缺失、重复和易位，材料和方法我们进行了基于阵列的比较基因组杂交分析，以检测自闭症谱系障碍（ASD）患者基因组DNA的拷贝数变异（CNVs）。他们被连续招募到我们的ASD分子遗传学研究中。核型分析，荧光原位杂交分析，和真实的时间定量PCR被用于验证tests.Results我们完成了全基因组CNV分析335例ASD从台湾。3例无血缘关系的男性患者在22q13.3分别携带3种不同的CNV，包括22q13.33处的106 kb的从头末端缺失、22q13.32-q13.33处的1.8Mb的从头间质重复和22q13.33处的147 kb的微缺失。这三种CNV均涉及SHANK 3基因的剂量变化。最后一名患者在19q13.42-q13.4处也携带了类似于3.86Mb的基因组重复，以及在22q13.33处类似于147 kb的微缺失。他的妹妹也携带这两个CNV，但她有发育迟缓和其他神经缺陷，没有ASD。结论ASD患者22 q13. 3位点的基因组重排是ASD遗传背景的一部分，SHANK 3剂量的改变与ASD的发生有关。然而，22q13.3重排患者的临床症状可能会因其他遗传和非遗传因素而异，而不限于该区域中涉及CNV的基因。版权所有（C）2017威科医疗集团All rights reserved.
Objectives Chromosome 22q13 is a hot region of genomic rearrangements that may result in deletion, duplication, and translocation, and that may lead to neurodevelopmental disorders in affected patients.Materials and methods We carried out an array-based comparative genomic hybridization analysis to detect copy number variations (CNVs) of genomic DNA in patients with autism spectrum disorders (ASD) who were consecutively recruited into our molecular genetic study of ASD. Karyotyping, fluorescent in-situ hybridization analysis, and real time-quantitative PCR were used for validation tests.Results We completed a genome-wide CNV analysis of 335 patients with ASD from Taiwan. Three unrelated male patients were found to carry three different CNVs at 22q13.3, respectively, including a de novo terminal deletion of similar to 106 kb at 22q13.33, a de novo interstitial duplication of similar to 1.8Mb at 22q13.32-q13.33, and a microdeletion of similar to 147 kb at 22q13.33. These three CNVs all involved the dosage change of the SHANK3 gene. The last patient also carried a genomic duplication of similar to 3.86Mb at 19q13.42-q13.4 in addition to a microdeletion of similar to 147 kb at 22q13.33. His younger sister also carried these two CNVs, but she had developmental delay and other neurological deficits without ASD. These two CNVs were transmitted from their unaffected father, who carried a balanced translocation between chromosome 22q and 19q.Conclusion Our data support that recurrent genomic rearrangements at 22q13.3 are part of the genetic landscape of ASD in our patients and changes in SHANK3 dosage are associated with neurodevelopmental disorders. However, the clinical symptoms of patients with 22q13.3 rearrangements can vary depending on other genetic and nongenetic factors, not limited to genes involved in CNVs in this region. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.