Granata Paola, Zito Alessandra, Cocciadiferro Dario, Novelli Antonio, Pessina Chiara, Mazza Tommaso, Ferri Matteo, Piccinelli Paolo, Luoni Chiara, Termine Cristiano, Fasano Mauro, Casalone Rosario
Cytogenetics and Medical Genetics Unit, Department of Services, ASST dei Sette Laghi, Varese, Italy.
School of Medical Genetics, Department of Medicine and Surgery, University of Insubria, Varese, Italy.
BMC Genomics. 2024 Dec 10;25(1):1186. doi: 10.1186/s12864-024-11077-5.
Autistic Spectrum Disorder (ASD) is a neurodevelopmental disorder with a strong genetic component and high heterogeneity. Essential ASD refers to patients who do not have other comorbidities. This study aimed to investigate the genetic basis of essential ASD using whole exome sequencing (WES) and array-comparative genomic hybridization (array-CGH).
In a cohort of 122 children with essential ASD, WES detected 382 variants across 223 genes, while array-CGH identified 46 copy number variants (CNVs). The combined use of WES and array-CGH revealed pathogenic variants in four patients (3.1% detection rate) and likely pathogenic variants in 34 patients (27.8% detection rate). Only one patient had a pathogenic CNV (0.8% detection rate). Including likely pathogenic variants, the overall detection rate was 31.2%. Additionally, 33 de novo heterozygous sequence variants were identified by WES, with three classified as pathogenic and 13 as likely pathogenic. Sequence variants were found in 85 genes already associated with ASD, and 138 genes not previously included in the SFARI dataset were identified as potential new candidate genes.
The study enhances genetic understanding of essential ASD and identifies new candidate genes of interest. The findings suggest that using both array-CGH and WES in patients with essential ASD can improve the detection of pathogenic and likely pathogenic genetic variants, contributing to better diagnosis and potentially guiding future research and treatment strategies.
自闭症谱系障碍（ASD）是一种具有强大遗传成分和高度异质性的神经发育障碍。特发性ASD是指没有其他合并症的患者。本研究旨在使用全外显子组测序（WES）和阵列比较基因组杂交（array-CGH）来研究特发性ASD的遗传基础。
在一个由122名特发性ASD儿童组成的队列中，WES在223个基因中检测到382个变异，而array-CGH鉴定出46个拷贝数变异（CNV）。WES和array-CGH的联合使用在4名患者中发现了致病变异（检测率3.1%），在34名患者中发现了可能的致病变异（检测率27.8%）。只有一名患者有一个致病性CNV（检测率0.8%）。包括可能的致病变异在内，总体检测率为31.2%。此外，WES鉴定出33个新生杂合序列变异，其中3个被分类为致病性变异，13个被分类为可能的致病变异。在85个已经与ASD相关的基因中发现了序列变异，并且鉴定出138个以前未包含在SFARI数据集中的基因作为潜在的新候选基因。
该研究增强了对特发性ASD的遗传理解，并确定了新的感兴趣的候选基因。研究结果表明，在特发性ASD患者中同时使用array-CGH和WES可以提高对致病性和可能的致病变异的检测，有助于更好的诊断，并可能指导未来的研究和治疗策略。
