The Role of Parental Cognitive, Behavioral, and Motor Profiles in Clinical Variability in Individuals With Chromosome 16p11.2 Deletions
The Role of Parental Cognitive, Behavioral, and Motor Profiles in Clinical Variability in Individuals With Chromosome 16p11.2 Deletions
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DOI：
10.1001/jamapsychiatry.2014.2147
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发表时间：
2015-02-01
期刊：
影响因子：
25.8
通讯作者：
Ledbetter, David H.
中科院分区：
文献类型：
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作者：
Moreno-De-Luca, Andres;Evans, David W.;Ledbetter, David H.
重要性由拷贝数变异（CNVs）引起的大多数疾病显示出显著的临床变异性，通常被称为不完全表达和可变表达。目的研究具有涉及相同基因组区域的CNVs的先证者中表型变异的贡献者;测量从头突变事件的效应量;并探讨家族背景对新发CNVs先证者认知、行为和运动表现结果的影响。设计，环境，和参与者以家庭为基础的研究设计，志愿者样本为56名16p11.2从头缺失的个体及其非携带者父母和兄弟姐妹，来自Simons个体变异项目。模型分析以测量效应量和组内相关性，以确定新发CNV的家庭背景对代表以下3个神经发育领域的数量性状的影响：认知能力（全量表智商）、社会行为（社会反应量表）和神经运动表现（普渡钉板测试）。我们包括一个人体测量性状，身体质量指数，comparation.RESULTS一个显着的有害影响，16p11.2删除在所有领域都表现出来。相对于双亲平均值，认知能力的效应量为-1.7 SD，社会行为为2.2 SD，神经运动表现为-1.3 SD（P < .001）。尽管有很大的有害影响，但父母和先证者之间的全面智商（0.42 [P = .03]）、言语智商（0.53 [P = .004]）和社会反应量表（0.52 [P = .009]）得分仍保持显著正相关。我们还观察到，与同胞相比，先证者的体重指数增加了1-SD，组内相关性为0.40（P = 0.07）。结论和相关性分析的家庭与从头CNVs提供了最少的混淆估计的影响大小的16p11.2删除遗传，数量性状，并证明了1至2 SD的影响，在所有的神经发育方面。显着的父母先证者的相关性表明，家庭背景有助于在这种和其他CNV疾病中看到的表型变异性，并可能对咨询家庭有关他们的孩子的发育和精神疾病的影响。使用双亲平均得分而不是一般人群平均得分可能更相关的突变或任何其他原因的性状变异对神经发育结果的影响，并可能对发育障碍的诊断和性状确定系统。
IMPORTANCE Most disorders caused by copy number variants (CNVs) display significant clinical variability, often referred to as incomplete penetrance and variable expressivity. Genetic and environmental sources of this variability are not well understood.OBJECTIVES To investigate the contributors to phenotypic variability in probands with CNVs involving the same genomic region; to measure the effect size for de novo mutation events; and to explore the contribution of familial background to resulting cognitive, behavioral, and motor performance outcomes in probands with de novo CNVs.DESIGN, SETTING, AND PARTICIPANTS Family-based study design with a volunteer sample of 56 individuals with de novo 16p11.2 deletions and their noncarrier parents and siblings from the Simons Variation in Individuals Project.MAIN OUTCOMES AND MEASURES We used linear mixed-model analysis to measure effect size and intraclass correlation to determine the influence of family background for a de novo CNV on quantitative traits representing the following 3 neurodevelopmental domains: cognitive ability (Full-Scale IQ), social behavior (Social Responsiveness Scale), and neuromotor performance (Purdue Pegboard Test). We included an anthropometric trait, body mass index, for comparison.RESULTS A significant deleterious effect of the 16p11.2 deletion was demonstrated across all domains. Relative to the biparental mean, the effect sizes were -1.7 SD for cognitive ability, 2.2 SD for social behavior, and -1.3 SD for neuromotor performance (P < .001). Despite large deleterious effects, significant positive correlations between parents and probands were preserved for the Full-Scale IQ (0.42 [P = .03]), the verbal IQ (0.53 [P = .004]), and the Social Responsiveness Scale (0.52 [P = .009]) scores. We also observed a 1-SD increase in the body mass index of probands compared with siblings, with an intraclass correlation of 0.40 (P = .07).CONCLUSIONS AND RELEVANCE Analysis of families with de novo CNVs provides the least confounded estimate of the effect size of the 16p11.2 deletion on heritable, quantitative traits and demonstrates a 1- to 2-SD effect across all neurodevelopmental dimensions. Significant parent-proband correlations indicate that family background contributes to the phenotypic variability seen in this and perhaps other CNV disorders and may have implications for counseling families regarding their children's developmental and psychiatric prognoses. Use of biparental mean scores rather than general population mean scores may be more relevant to examine the effect of a mutation or any other cause of trait variation on a neurodevelopmental outcome and possibly on systems of diagnosis and trait ascertainment for developmental disorders.