Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California, USA.
Neuroscience Interdepartmental Program, University of California, Los Angeles, California, USA.
Autism Res. 2023 Dec;16(12):2247-2262. doi: 10.1002/aur.3049. Epub 2023 Nov 23.
Rare genetic variants that confer large effects on neurodevelopment and behavioral phenotypes can reveal novel gene-brain-behavior relationships relevant to autism. Copy number variation at the 22q11.2 locus offer one compelling example, as both the 22q11.2 deletion (22qDel) and duplication (22qDup) confer increased likelihood of autism spectrum disorders (ASD) and cognitive deficits, but only 22qDel confers increased psychosis risk. Here, we used the Penn Computerized Neurocognitive Battery (Penn-CNB) to characterized neurocognitive profiles of 126 individuals: 55 22qDel carriers (M = 19.2 years, 49.1% male), 30 22qDup carriers (M = 17.3 years, 53.3% male), and 41 typically developing (TD) subjects (M = 17.3 years, 39.0% male). We performed linear mixed models to assess group differences in overall neurocognitive profiles, domain scores, and individual test scores. We found all three groups exhibited distinct overall neurocognitive profiles. 22qDel and 22qDup carriers showed significant accuracy deficits across all domains relative to controls (episodic memory, executive function, complex cognition, social cognition, and sensorimotor speed), with 22qDel carriers exhibiting more severe accuracy deficits, particularly in episodic memory. However, 22qDup carriers generally showed greater slowing than 22qDel carriers. Notably, slower social cognition speed was uniquely associated with increased global psychopathology and poorer psychosocial functioning in 22qDup. Compared to TD, 22q11.2 copy number variants (CNV) carriers failed to show age-associated improvements in multiple cognitive domains. Exploratory analyses revealed 22q11.2 CNV carriers with ASD exhibited differential neurocognitive profiles, based on 22q11.2 copy number. These results suggest that there are distinct neurocognitive profiles associated with either a loss or gain of genomic material at the 22q11.2 locus.
罕见的遗传变异会对神经发育和行为表型产生较大影响，可以揭示与自闭症相关的新的基因-大脑-行为关系。22q11.2 基因座的拷贝数变异就是一个引人注目的例子，22q11.2 缺失（22qDel）和重复（22qDup）都增加了自闭症谱系障碍（ASD）和认知缺陷的可能性，但只有 22qDel 增加了患精神病的风险。在这里，我们使用宾夕法尼亚计算机神经认知测试（Penn-CNB）来描述 126 名个体的神经认知特征：55 名 22qDel 携带者（M=19.2 岁，49.1%为男性）、30 名 22qDup 携带者（M=17.3 岁，53.3%为男性）和 41 名正常发育（TD）个体（M=17.3 岁，39.0%为男性）。我们进行了线性混合模型分析，以评估三组在整体神经认知特征、各领域评分和个体测试得分方面的差异。我们发现三组个体的整体神经认知特征明显不同。22qDel 和 22qDup 携带者在所有领域的准确性都显著低于对照组（情景记忆、执行功能、复杂认知、社会认知和感觉运动速度），22qDel 携带者的准确性缺陷更为严重，特别是在情景记忆方面。然而，22qDup 携带者通常比 22qDel 携带者表现出更大的减速。值得注意的是，较慢的社会认知速度与 22qDup 中更高的整体精神病理学和较差的社会心理功能有关。与 TD 相比，22q11.2 拷贝数变异（CNV）携带者在多个认知领域未能表现出与年龄相关的改善。探索性分析显示，根据 22q11.2 拷贝数，患有自闭症的 22q11.2 CNV 携带者表现出不同的神经认知特征。这些结果表明，22q11.2 基因座的基因组物质缺失或获得与特定的神经认知特征有关。
