Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2.
Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2.
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DOI：
10.1002/aur.1378
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发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Kim SJ
中科院分区：
文献类型：
--
作者：
Chaste P;Sanders SJ;Mohan KN;Klei L;Song Y;Murtha MT;Hus V;Lowe JK;Willsey AJ;Moreno-De-Luca D;Yu TW;Fombonne E;Geschwind D;Grice DE;Ledbetter DH;Lord C;Mane SM;Martin DM;Morrow EM;Walsh CA;Sutcliffe JS;State MW;Martin CL;Devlin B;Beaudet AL;Cook EH Jr;Kim SJ
除了性染色体，人类基因组中的所有其他位置都普遍认为，每个位置会遗传两个副本，一个来自母亲，一个来自父亲。然而，随着对基因组的描述越来越精细，我们现在知道这一规则可以被打破。当规则被打破时，我们说该区域有拷贝数变体或CNV。这些CNV可以从头产生，也可以遗传，它们可能是无害的，也可能增加疾病的风险。15号染色体上长臂着丝粒附近的一个特定区域(即15q11.2-q13)是CNV的热点，它有几个断裂点(BP)。在该区域观察到的重排中，来自常见BP1和BP2之间的CNV被报道与包括自闭症谱系障碍(ASD)在内的发育障碍有关。然而，它对ASD风险的影响虽然可能很小，但还没有完全表现出来，因此对复发风险咨询提出了挑战。我们在一个具有良好特征的ASD样本Simons Simplex Collection中评估了它对风险和ASD相关表型的影响。我们发现，BP1-BP2 CNV对风险的贡献很小，对ASD相关性状的影响也同样很小。为了与目前美国医学遗传学学会关于解释出生后CNV的指南一致，BP1-BP2缺失和复制CNV可能最好被归类为不确定意义的变体(VOU)：它们似乎对风险有影响，但由于影响太小，这些CNV不具有致病地位。15号染色体近端区域是拷贝数变异(CNV)的基因组热点之一。在该区域观察到的重排中，来自公共断裂点1和2(BP1和BP2)之间的CNV已被报道与自闭症谱系障碍(ASD)共分离。尽管支持BP1-BP2 CNV与自闭症之间联系的证据越来越多，但BP1-BP2 CNV的影响程度仍然难以捉摸，这对复发风险咨询提出了巨大的挑战。为了进一步了解它们对ASD的致病性，我们在一个有良好特征的ASD样本(n=2525个家系)中估计了ASD的BP1-BP2 CNV的外显率以及它们对ASD相关表型的影响。TDT仅对先证者(20T：9nT)的重复染色体有显著的优先传递。ASD的BP1-BP2 CNV的外显率很低，增加了0.3%(缺失)和0.8%(复制)的额外风险。逐步回归分析表明，在男性和母亲遗传时，CNV对ASD相关表型的影响更大。综上所述，这些结果与BP1-BP2 CNV作为自闭症危险因素的结果是一致的。然而，它们的影响是温和的，更类似于常见变种的影响。为了与目前美国医学遗传学学会关于解释出生后CNV的指南一致，BP1-BP2缺失和复制CNV可能最好被归类为不确定意义的变体(VOU)：它们似乎对风险有影响，但由于影响太小，这些CNV不具有致病地位。
Aside from the sex chromosome, all other locations in the human genome have the general expectation that two copies per location are inherited, one from mother and one from father. Yet, with finer and finer characterization of the genome we now know that this rule can be broken. When the rule is broken, we say the region has a copy number variant or CNV. These CNVs can arise de novo or can be inherited and they can be harmless or increase risk for disease. A particular region of chromosome 15, near the centromere on the long arm (i.e., 15q11.2-q13), is a hotspot for CNVs and it has several breakpoints (BP). Among the rearrangements observed in this region, CNVs from the interval between the common BP1 and BP2 have been reported to be associated with developmental disorders, including autism spectrum disorder (ASD). Yet its effect on risk for ASD, while likely to be small, is not fully characterized and thus poses a challenge to recurrence-risk counseling. We estimated its effect on risk and ASD-related phenotypes in a well-characterized ASD sample, the Simons Simplex Collection. We find that BP1-BP2 CNVs contribute only modestly to risk and have similarly small effect on traits related to ASD. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status. The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD related phenotypes in a well-characterized ASD sample (n=2,525 families). TDT revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyzes suggest a greater effect of the CNVs on ASD related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.
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影响因子：
3.9
作者：
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通讯作者：
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影响因子：
2.1
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