Department of Psychiatry and Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Transl Psychiatry. 2022 Mar 9;12(1):97. doi: 10.1038/s41398-022-01859-4.
The 22q11.2 deletion syndrome (22q11.2DS) is characterized by a well-defined microdeletion and is associated with increased risk of neurodevelopmental phenotypes including autism spectrum disorders (ASD) and intellectual impairment. The typically deleted region in 22q11.2DS contains multiple genes with the potential of altering metabolism. Deficits in metabolic processes during early brain development may help explain the increased prevalence of neurodevelopmental phenotypes seen in 22q11.2DS. However, relatively little is known about the metabolic impact of the 22q11.2 deletion, while such insight may lead to increased understanding of the etiology. We performed untargeted metabolic analysis in a large sample of dried blood spots derived from 49 22q11.2DS patients and 87 controls, to identify a metabolic signature for 22q11.2DS. We also examined trait-specific metabolomic patterns within 22q11.2DS patients, focusing on intelligence (intelligence quotient, IQ) and ASD. We used the Boruta algorithm to select metabolites distinguishing patients from controls, patients with ASD from patients without, and patients with an IQ score in the lowest range from patients with an IQ score in the highest range. The relevance of the selected metabolites was visualized with principal component score plots, after which random forest analysis and logistic regression were used to measure predictive performance of the selected metabolites. Analysis yielded a distinct metabolic signature for 22q11.2DS as compared to controls, and trait-specific (IQ and ASD) metabolomic patterns within 22q11.2DS patients. The metabolic characteristics of 22q11.2DS provide insights in biological mechanisms underlying the neurodevelopmental phenotype and may ultimately aid in identifying novel therapeutic targets for patients with developmental disorders.
22q11.2 缺失综合征（22q11.2DS）的特征是明确的微缺失，并与神经发育表型的风险增加有关，包括自闭症谱系障碍（ASD）和智力障碍。22q11.2DS 中典型缺失的区域包含多个具有改变代谢能力的基因。在大脑早期发育过程中代谢过程的缺陷可能有助于解释 22q11.2DS 中神经发育表型的高发率。然而，对于 22q11.2 缺失的代谢影响相对了解较少，而这种见解可能会增加对病因的理解。我们对来自 49 名 22q11.2DS 患者和 87 名对照的大量干血斑进行了非靶向代谢分析，以确定 22q11.2DS 的代谢特征。我们还检查了 22q11.2DS 患者的特定表型代谢模式，重点关注智力（智商，IQ）和 ASD。我们使用 Boruta 算法选择将患者与对照、患有 ASD 的患者与未患有 ASD 的患者以及 IQ 得分最低的患者与 IQ 得分最高的患者区分开来的代谢物。使用主成分得分图可视化所选代谢物的相关性，然后使用随机森林分析和逻辑回归来测量所选代谢物的预测性能。分析产生了 22q11.2DS 与对照相比的独特代谢特征，以及 22q11.2DS 患者内的特定表型（IQ 和 ASD）代谢模式。22q11.2DS 的代谢特征为神经发育表型的生物学机制提供了深入的了解，并最终可能有助于为发育障碍患者确定新的治疗靶点。
