D'Angelo Debra, Lebon Sébastien, Chen Qixuan, Martin-Brevet Sandra, Snyder LeeAnne Green, Hippolyte Loyse, Hanson Ellen, Maillard Anne M, Faucett W Andrew, Macé Aurélien, Pain Aurélie, Bernier Raphael, Chawner Samuel J R A, David Albert, Andrieux Joris, Aylward Elizabeth, Baujat Genevieve, Caldeira Ines, Conus Philippe, Ferrari Carrina, Forzano Francesca, Gérard Marion, Goin-Kochel Robin P, Grant Ellen, Hunter Jill V, Isidor Bertrand, Jacquette Aurélia, Jønch Aia E, Keren Boris, Lacombe Didier, Le Caignec Cédric, Martin Christa Lese, Männik Katrin, Metspalu Andres, Mignot Cyril, Mukherjee Pratik, Owen Michael J, Passeggeri Marzia, Rooryck-Thambo Caroline, Rosenfeld Jill A, Spence Sarah J, Steinman Kyle J, Tjernagel Jennifer, Van Haelst Mieke, Shen Yiping, Draganski Bogdan, Sherr Elliott H, Ledbetter David H, van den Bree Marianne B M, Beckmann Jacques S, Spiro John E, Reymond Alexandre, Jacquemont Sébastien, Chung Wendy K
Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York.
Pediatric Neurology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
JAMA Psychiatry. 2016 Jan;73(1):20-30. doi: 10.1001/jamapsychiatry.2015.2123.
The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI).
To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD.
DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives.
Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data.
Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies.
The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.
16p11.2 BP4 - BP5重复是与自闭症谱系障碍（ASD）、精神分裂症以及诸如体重指数（BMI）降低等合并症最常相关的拷贝数变异。
描述16p11.2重复对认知、行为、医学和人体测量学特征的影响，并通过系统比较重复携带者和相互缺失携带者（他们也有患ASD的风险）的结果来了解这些影响的特异性。
设计、设置和参与者：这项对1006名研究参与者的国际队列研究，将270名重复携带者与其102名家族内对照个体、390名相互缺失携带者以及来自欧洲和北美队列的244名缺失对照进行了比较。数据收集时间为2010年8月1日至2015年5月31日，并于2015年1月1日至8月14日进行分析。使用线性混合模型通过与非携带者亲属比较来估计重复和缺失对临床特征的影响。
全量表智商（FSIQ）、非言语智商和言语智商的结果；ASD或其他《精神疾病诊断与统计手册第四版》（DSM - IV）诊断的存在情况；BMI；头围；以及医学数据。
在1006名研究参与者中，重复与先证者携带者和非携带者亲属之间平均FSIQ得分低26.3分以及非先证者携带者中较低的平均FSIQ得分（16.2 - 11.4分）相关。缺失的总体平均效应相似（-22.1分；P <.001）。然而，发现FSIQ存在广泛差异，与缺失组相比，FSIQ得分极低（≤40）和高于平均水平（>100）的比例分别增加了19.4倍和2.0倍（P <.001）。父母的FSIQ预测了这种变异的一部分（遗传性先证者中约为36.0%）。虽然缺失和重复先证者携带者中ASD的发生率相似（分别为16.0%和20.0%），但患有ASD的重复先证者的FSIQ显著更低（低26.3分）。重复携带者的头围和BMI测量值也较低，这与先前研究的结果一致。
重复对认知的平均影响与相互缺失相似，但重复的方差显著更高，缺失未观察到严重和轻度亚组。这些结果表明，其他遗传和家族因素导致了这种变异性。需要进一步研究来确定认知缺陷的预测因素。
