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首页> 外文期刊>BMC Medical Genomics >Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: Efficient identification of known microduplications and identification of a novel microduplication in ASMT
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Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: Efficient identification of known microduplications and identification of a novel microduplication in ASMT

机译：用于自闭症谱系障碍基因筛查的多重结扎依赖性探针扩增：有效识别已知的微复制和ASMT中新型的微复制

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Background It has previously been shown that specific microdeletions and microduplications, many of which also associated with cognitive impairment (CI), can present with autism spectrum disorders (ASDs). Multiplex ligation-dependent probe amplification (MLPA) represents an efficient method to screen for such recurrent microdeletions and microduplications. Methods In the current study, a total of 279 unrelated subjects ascertained for ASDs were screened for genomic disorders associated with CI using MLPA. Fluorescence in situ hybridization (FISH), quantitative polymerase chain reaction (Q-PCR) and/or direct DNA sequencing were used to validate potential microdeletions and microduplications. Methylation-sensitive MLPA was used to characterize individuals with duplications in the Prader-Willi/Angelman (PWA) region. Results MLPA showed two subjects with typical ASD-associated interstitial duplications of the 15q11-q13 PWA region of maternal origin. Two additional subjects showed smaller, de novo duplications of the PWA region that had not been previously characterized. Genes in these two novel duplications include GABRB3 and ATP10A in one case, and MKRN3 , MAGEL2 and NDN in the other. In addition, two subjects showed duplications of the 22q11/DiGeorge syndrome region. One individual was found to carry a 12 kb deletion in one copy of the ASPA gene on 17p13, which when mutated in both alleles leads to Canavan disease. Two subjects showed partial duplication of the TM4SF2 gene on Xp11.4, previously implicated in X-linked non-specific mental retardation, but in our subsequent analyses such variants were also found in controls. A partial duplication in the ASMT gene, located in the pseudoautosomal region 1 (PAR1) of the sex chromosomes and previously suggested to be involved in ASD susceptibility, was observed in 6–7% of the cases but in only 2% of controls (P = 0.003). Conclusion MLPA proves to be an efficient method to screen for chromosomal abnormalities. We identified duplications in 15q11-q13 and in 22q11, including new de novo small duplications, as likely contributing to ASD in the current sample by increasing liability and/or exacerbating symptoms. Our data indicate that duplications in TM4SF2 are not associated with the phenotype given their presence in controls. The results in PAR1/PAR2 are the first large-scale studies of gene dosage in these regions, and the findings at the ASMT locus indicate that further studies of the duplication of the ASMT gene are needed in order to gain insight into its potential involvement in ASD. Our studies also identify some limitations of MLPA, where single base changes in probe binding sequences alter results. In summary, our studies indicate that MLPA, with a focus on accepted medical genetic conditions, may be an inexpensive method for detection of microdeletions and microduplications in ASD patients for purposes of genetic counselling if MLPA-identified deletions are validated by additional methods.
机译：背景技术以前已经显示出特定的微缺失和微复制，其中许多也与认知障碍（CI）有关，可能会出现自闭症谱系障碍（ASD）。多重连接依赖性探针扩增（MLPA）代表了一种有效的方法，可筛选此类复发性微缺失和微重复。方法在本研究中，使用MLPA对总共279名ASD确诊的无关受试者进行了筛查与CI相关的基因组疾病。荧光原位杂交（FISH），定量聚合酶链反应（Q-PCR）和/或直接DNA测序用于验证潜在的微缺失和微复制。甲基化敏感的MLPA用于表征在Prader-Willi / Angelman（PWA）地区重复的个体。结果MLPA显示两名受试者的母亲起源的15q11-q13 PWA区具有典型的ASD相关的组织间质重复。另外两个主题显示了以前没有特征的，较小的，从头开始的PWA区域重复。这两个新颖的重复中的基因在一种情况下包括GABRB3和ATP10A，在另一种情况下包括MKRN3，MAGEL2和NDN。此外，两名受试者显示22q11 / DiGeorge综合征区域重复。发现一个人在17p13的ASPA基因的一个拷贝中带有12 kb的缺失，当在两个等位基因中突变时都会导致Canavan病。两名受试者在Xp11.4上显示了TM4SF2基因的部分重复，该基因先前与X连锁的非特异性智力低下有关，但在我们随后的分析中，此类变体也在对照中发现。在6–7％的病例中观察到了ASMT基因的部分重复，该基因位于性染色体的伪常染色体区域1（PAR1）中，以前被认为与ASD易感性有关，但在对照组中只有2％（P = 0.003）。结论MLPA被证明是筛查染色体异常的有效方法。我们确定了15q11-q13和22q11中的重复，包括新的从头开始的小重复，可能通过增加责任和/或加剧症状而导致当前样本中的ASD。我们的数据表明，TM4SF2中的重复与表型无关，因为它们存在于对照中。 PAR1 / PAR2的结果是这些区域中基因剂量的首次大规模研究，并且ASMT基因座处的发现表明，需要进一步研究ASMT基因的重复，以便深入了解ASMT基因可能参与其中。 ASD。我们的研究还确定了MLPA的一些局限性，其中探针结合序列的单碱基改变会改变结果。总而言之，我们的研究表明，如果通过其他方法验证了MLPA识别的缺失，那么以遗传医学为重点的MLPA可能是一种便宜的检测ASD患者微缺失和微复制的方法，可以进行遗传咨询。

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