Disorders of gene dosage can significantly increase risk for psychopathology, but outcomes vary greatly amongst carriers of any given chromosomal aneuploidy or sub-chromosomal copy number variation (CNV). One potential path to advance precision medicine for neurogenetic disorders is modeling penetrance in probands relative to observed phenotypes in their non-carrier relatives. Here, we seek to advance this general analytic framework by developing new methods in application to XYY syndrome—a sex chromosome aneuploidy that is known to increase risk for psychopathology. We analyzed a range of cognitive and behavioral domains in XYY probands and their non-carrier family members (n = 58 families), including general cognitive ability (FSIQ), as well as continuous measures of traits related to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Proband and relative scores were compared using covariance, regression and cluster analysis. Comparisons were made both within and across traits. Proband scores were shifted away from family scores with effect sizes varying between 0.9 and 2.4 across traits. Only FSIQ and vocabulary scores showed a significant positive correlation between probands and their non-carrier relatives across families (R2 ~ 0.4). Variability in family FSIQ also cross-predicted variability in proband ASD trait severity. Cluster analysis across all trait-relative pairings revealed that variability in parental psychopathology was more weakly coupled to their XYY versus their euploid offspring. We present a suite of generalizable methods for modeling variable penetrance in aneuploidy and CNV carriers using family data. These methods update estimates of phenotypic penetrance for XYY and suggest that the predictive utility of family data is likely to vary for different traits and different gene dosage disorders. ClinicalTrials.gov NCT00001246 , “89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls.” Date of registry: 01 October 1989.

中文翻译：

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对神经遗传性疾病先证者结果的家族预测因子建模：在 XYY 综合征中的初步应用

基因剂量紊乱会显着增加精神病理学的风险，但结果在任何给定染色体非整倍体或亚染色体拷贝数变异 (CNV) 的携带者之间差异很大。推进神经遗传性疾病精准医学的一种潜在途径是模拟先证者的外显率，相对于其非携带者亲属中观察到的表型。在这里，我们寻求通过开发适用于 XYY 综合征（一种已知会增加精神病理学风险的性染色体非整倍性）的新方法来推进这一一般分析框架。我们分析了 XYY 先证者及其非携带者家庭成员（n = 58 个家庭）的一系列认知和行为领域，包括一般认知能力 (FSIQ)、以及对自闭症谱系障碍 (ASD) 和注意力缺陷多动障碍 (ADHD) 相关特征的连续测量。使用协方差、回归和聚类分析比较先证者和相对分数。在性状内和性状之间进行了比较。先证者分数从家庭分数转移，影响大小在 0.9 和 2.4 之间变化。只有 FSIQ 和词汇分数显示先证者与其非携带者亲属之间存在显着的正相关（R2 ~ 0.4）。家庭 FSIQ 的变异性也交叉预测了先证者 ASD 性状严重性的变异性。对所有性状相关配对的聚类分析显示，与整倍体后代相比，父母精神病理学的变异性与其 XYY 的耦合更弱。我们提出了一套通用的方法，用于使用家族数据对非整倍体和 CNV 携带者的可变外显率进行建模。这些方法更新了 XYY 表型外显率的估计值，并表明家族数据的预测效用可能因不同的性状和不同的基因剂量障碍而有所不同。ClinicalTrials.gov NCT00001246，“89-M-0006：儿童期精神疾病、内分泌疾病和健康控制的脑成像。” 登记日期：1989 年 10 月 1 日。儿童期精神疾病、内分泌疾病和健康控制的脑成像。” 登记日期：1989 年 10 月 1 日。儿童期精神疾病、内分泌疾病和健康控制的脑成像。” 登记日期：1989 年 10 月 1 日。