Abstract：
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with considerable genetic heterogeneity. The disorder is clinically diagnosed based on DSM-5 criteria, featuring deficits in social communication and interaction, along with restricted and repetitive behaviours. Here, we performed whole-genome sequencing (WGS) on four individuals with ASD from two multiplex families (MPX), where more than one individual is affected, to identify potential single nucleotide variants (SNVs) and structural variants (SVs) in coding and non-coding regions. A rigorous bioinformatics pipeline was employed for variant detection, followed by segregation analysis. Our investigation revealed an unreported splicing variant in the DYRK1A gene (c.-77 + 2T > C; IVS1 + 2T > C; NM_001396.5), in heterozygote form in two affected children in one of the families (family B), which was absent in the healthy parents and siblings. This finding suggests the presence of gonadal mosaicism in one of the parents, representing the first documented instance of such inheritance for a variant in the DYRK1A gene associated with ASD. Furthermore, we identified a 50 bp deletion in intron 9 of the DLG2 gene in two affected patients from the same family, confirmed by PCR and Sanger sequencing. In Family A, we identified potential candidate variants associated with ASD shared by the two patients. These findings enhance our understanding of the genetic landscape of ASD, particularly in MPX families, and highlight the utility of WGS in uncovering novel genetic contributions to neurodevelopmental disorders.
摘要：
自闭症谱系障碍（ASD）是一种复杂的神经发育疾病，具有相当大的遗传异质性。该疾病根据DSM-5标准进行临床诊断，以社会交往和互动的缺陷为特征，以及受限制和重复的行为。这里,我们对来自两个多重家族（MPX）的四个患有ASD的个体进行了全基因组测序（WGS），不止一个人受到影响，在编码区和非编码区中鉴定潜在的单核苷酸变体(SNV)和结构变体(SV)。采用严格的生物信息学管道进行变异检测，其次是隔离分析。我们的调查显示DYRK1A基因中有一个未报道的剪接变体（c。-77+2T>C;IVS1+2T>C;NM_001396.5),在其中一个家庭（家庭B）中的两个受影响儿童的杂合子形式中，这在健康的父母和兄弟姐妹中是不存在的。这一发现表明父母之一存在性腺镶嵌，代表与ASD相关的DYRK1A基因中的变体的这种遗传的第一个记录实例。此外，我们在来自同一家族的两个受影响的患者中发现了DLG2基因内含子9中50bp的缺失，通过PCR和Sanger测序证实。在家庭A,我们确定了两名患者共有的与ASD相关的潜在候选变异.这些发现增强了我们对ASD遗传景观的理解，特别是在MPX家族中，并强调WGS在揭示神经发育障碍的新遗传贡献中的实用性。
