Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Genetics & Genome Biology Program, The Hospital for Sick Children, 686 Bay St., Toronto, ON, M5G 0A4, Canada.
Orphanet J Rare Dis. 2021 Jan 6;16(1):6. doi: 10.1186/s13023-020-01648-6.
7q11.23 duplication (Dup7) is one of the most frequent recurrent copy number variants (CNVs) in individuals with autism spectrum disorder (ASD), but based on gold-standard assessments, only 19% of Dup7 carriers have ASD, suggesting that additional genetic factors are necessary to manifest the ASD phenotype. To assess the contribution of additional genetic variants to the Dup7 phenotype, we conducted whole-genome sequencing analysis of 20 Dup7 carriers: nine with ASD (Dup7-ASD) and 11 without ASD (Dup7-non-ASD).
We identified three rare variants of potential clinical relevance for ASD: a 1q21.1 microdeletion (Dup7-non-ASD) and two deletions which disrupted IMMP2L (one Dup7-ASD, one Dup7-non-ASD). There were no significant differences in gene-set or pathway variant burden between the Dup7-ASD and Dup7-non-ASD groups. However, overall intellectual ability negatively correlated with the number of rare loss-of-function variants present in nervous system development and membrane component pathways, and adaptive behaviour standard scores negatively correlated with the number of low-frequency likely-damaging missense variants found in genes expressed in the prenatal human brain. ASD severity positively correlated with the number of low frequency loss-of-function variants impacting genes expressed at low levels in the brain, and genes with a low level of intolerance.
Our study suggests that in the presence of the same pathogenic Dup7 variant, rare and low frequency genetic variants act additively to contribute to components of the overall Dup7 phenotype.
7q11.23 重复（Dup7）是自闭症谱系障碍（ASD）患者中最常见的反复出现的拷贝数变异（CNV）之一，但基于金标准评估，只有 19%的 Dup7 携带者患有 ASD，这表明需要额外的遗传因素来表现出 ASD 表型。为了评估额外的遗传变异对 Dup7 表型的贡献，我们对 20 名 Dup7 携带者进行了全基因组测序分析：9 名患有 ASD（Dup7-ASD），11 名没有 ASD（Dup7-non-ASD）。
我们发现了三个可能与 ASD 相关的罕见变异：一个 1q21.1 微缺失（Dup7-non-ASD）和两个破坏 IMMP2L 的缺失（一个 Dup7-ASD，一个 Dup7-non-ASD）。Dup7-ASD 和 Dup7-non-ASD 组之间在基因集或通路变异负担方面没有显著差异。然而，总体智力能力与神经系统发育和膜成分途径中罕见的功能丧失变异数量呈负相关，适应性行为标准评分与产前人脑表达的基因中低频可能有害的错义变异数量呈负相关。ASD 严重程度与影响大脑中低水平表达基因的低频功能丧失变异数量呈正相关，与大脑中低水平耐受基因呈正相关。
我们的研究表明，在存在相同致病性 Dup7 变异的情况下，罕见的和低频的遗传变异以累加的方式作用于整体 Dup7 表型的各个组成部分。
