Joyce & Irving Goldman Medical School, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Department of Epidemiology, Biostatistics and Community Health Sciences, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
J Neurodev Disord. 2024 Sep 30;16(1):55. doi: 10.1186/s11689-024-09573-6.
Recent evidence suggests that certain fetal anomalies detected upon prenatal ultrasound screenings are associated with autism spectrum disorder (ASD). In this cross-sectional study, we aimed to identify genetic variants associated with fetal ultrasound anomalies (UFAs) in children with ASD.
The study included all children with ASD who are registered in the database of the Azrieli National Center of Autism and Neurodevelopment and for whom both prenatal ultrasound and whole exome sequencing (WES) data were available. We applied our in-house integrative bioinformatics pipeline, AutScore, to these WES data to prioritize rare, gene-disrupting variants (GDVs) probably contributing to ASD susceptibily. Univariate statistics and multivariable regression were used to assess the associations between UFAs and GDVs identified in these children.
The study sample comprised 126 children, of whom 43 (34.1%) had at least one UFA detected in the prenatal ultrasound scan. A total of 87 candidate ASD genetic variants were detected in 60 children, with 24 (40%) children carrying multiple variants. Children with UFAs were more likely to have loss-of-function (LoF) mutations (aOR = 2.55, 95%CI: 1.13-5.80). This association was particularly noticeable when children with structural anomalies or children with UFAs in their head and brain scans were compared to children without UFAs (any mutation: aOR = 8.28, 95%CI: 2.29-30.01; LoF: aOR = 5.72, 95%CI: 2.08-15.71 and any mutation: aOR = 6.39, 95%CI: 1.34-30.47; LoF: aOR = 4.50, 95%CI: 1.32-15.35, respectively). GDVs associated with UFAs were enriched in genes highly expressed across all tissues (aOR = 2.76, 95%CI: 1.14-6.68). There was a weak, but significant, correlation between the number of mutations and the number of abnormalities detected in the same children (r = 0.21, P = 0.016).
The results provide valuable insights into the potential genetic basis of prenatal organogenesis abnormalities associated with ASD and shed light on the complex interplay between genetic factors and fetal development.
最近的证据表明，产前超声筛查中发现的某些胎儿异常与自闭症谱系障碍（ASD）有关。在这项横断面研究中，我们旨在确定与 ASD 儿童的胎儿超声异常（UFAs）相关的遗传变异。
该研究纳入了数据库中所有登记的 ASD 儿童，这些儿童的产前超声和全外显子组测序（WES）数据均可用。我们应用内部整合生物信息学管道 AutScore，对这些 WES 数据进行优先级排序，以确定可能导致 ASD 易感性的罕见基因破坏性变异（GDV）。采用单变量统计和多变量回归评估 UFAs 与这些儿童中发现的 GDV 之间的关联。
研究样本包括 126 名儿童，其中 43 名（34.1%）在产前超声扫描中至少发现一种 UFA。在 60 名儿童中检测到 87 个候选 ASD 遗传变异，其中 24 名（40%）儿童携带多种变异。有 UFAs 的儿童更有可能携带功能丧失（LoF）突变（aOR=2.55，95%CI：1.13-5.80）。当将具有结构异常或头部和脑部扫描 UFAs 的儿童与无 UFAs 的儿童进行比较时，这种关联更为明显（任何突变：aOR=8.28，95%CI：2.29-30.01；LoF：aOR=5.72，95%CI：2.08-15.71 和任何突变：aOR=6.39，95%CI：1.34-30.47；LoF：aOR=4.50，95%CI：1.32-15.35）。与 UFAs 相关的 GDVs 在所有组织中高表达的基因中富集（aOR=2.76，95%CI：1.14-6.68）。在同一儿童中，突变数量与异常数量之间存在微弱但显著的相关性（r=0.21，P=0.016）。
研究结果为与 ASD 相关的产前器官发生异常的潜在遗传基础提供了有价值的见解，并揭示了遗传因素与胎儿发育之间的复杂相互作用。
