A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants.
A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants.
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DOI：
10.1176/appi.ajp.2020.20010015
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发表时间：
2021-01-01
期刊：
影响因子：
--
通讯作者：
van den Bree MBM
中科院分区：
文献类型：
--
作者：
Chawner SJRA;Doherty JL;Anney RJL;Antshel KM;Bearden CE;Bernier R;Chung WK;Clements CC;Curran SR;Cuturilo G;Fiksinski AM;Gallagher L;Goin-Kochel RP;Gur RE;Hanson E;Jacquemont S;Kates WR;Kushan L;Maillard AM;McDonald-McGinn DM;Mihaljevic M;Miller JS;Moss H;Pejovic-Milovancevic M;Schultz RT;Green-Snyder L;Vorstman JA;Wenger TL;IMAGINE-ID Consortium;Hall J;Owen MJ;van den Bree MBM
某些拷贝数变异（CNVs）大大增加了自闭症的风险。我们进行了一项遗传学优先的研究，以调查自闭症临床表现的异质性是否受到特定基因型-表型关系的支持。这项国际研究包括547名个人（12.3岁（SD=4.2），54%男性），根据与自闭症高风险相关的罕见CNV基因诊断确定16p11.2缺失型82例，16p11.2重复型50例，22q11.2缺失型370例，22q11.2重复型45例，以及2027例不同病因的自闭症患者（9.1岁（SD=4.9），86%为男性）。进行了自闭症诊断访谈修订版（ADI-R）和智商测试。四个基因变异组在自闭症严重程度、自闭症亚领域特征以及智商特征上存在差异。然而，我们发现个体遗传变异组内的表型结果存在很大的变异性（74%至97%的变异取决于性状），而组间的变异性很低（1%至21%取决于性状）。我们比较了符合自闭症标准的CNV携带者与异质性自闭症个体，并确定了一系列特征差异。使用临床截止值，我们发现，54%的人与4个CNV之一谁不符合完整的自闭症诊断标准，但有自闭症特征的水平升高。许多CNV携带者不符合自闭症的完整诊断标准，但仍然符合自闭症特征的临床截止值。虽然我们发现变异体之间的特征差异，但同一变异体内的临床症状存在相当大的变异性。
Certain copy number variants (CNVs) greatly increase risk of autism. We conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships. This international study included 547 individuals (12.3 years (SD=4.2), 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers and 45 22q11.2 duplication carriers), as well as 2027 individuals (9.1 years (SD=4.9), 86% male) with autism of heterogeneous aetiology. The Autism Diagnostic Interview-Revised (ADI-R) and IQ testing were conducted. The four genetic variant groups differed in autism severity, autism subdomain profile as well as IQ profile. However, we found substantial variability in phenotypic outcome within individual genetic variant groups (74% to 97% of the variance depending on the trait), whereas variability between groups was low (1% to 21% depending on trait). We compared CNV carriers who met autism criteria, to individuals with heterogeneous autism, and a range of profile differences were identified. Using clinical cut-offs, we found that 54% of individuals with one of the 4 CNVs who did not meet full autism diagnostic criteria nonetheless had elevated levels of autistic traits. Many CNV carriers do not meet full diagnostic criteria for autism, but nevertheless meet clinical cut-offs for autistic traits. Although we find profile differences between variants, there is considerable variability in clinical symptoms within the same variant.
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影响因子：
3.7
作者：
Bruining H;de Sonneville L;Swaab H;de Jonge M;Kas M;van Engeland H;Vorstman J
通讯作者：
Vorstman J
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