Detection of genomic variants by genome sequencing in foetuses with central nervous system abnormalities

Clinical validity of genome sequencing (GS) (&gt;30×) has been preliminarily verified in the post-natal setting. This study is to investigate the potential utility of trio-GS as a prenatal test for diagnosis of central nervous system (CNS) anomalies. We performed trio-based GS on a prospective cohort of 17 foetuses with CNS abnormalities. Single nucleotide variation (SNV), small insertion and deletion (Indel), copy number variation (CNV), structural variant (SV), and regions with absence of heterozygosity (AOH) were analyzed and classified according to ACMG guidelines. Trio-GS identified diagnostic findings in 29.4% (5/17) of foetuses, with pathogenic variants found in <i>SON</i>, <i>L1CAM</i>, <i>KMT2D,</i> and <i>ASPM</i>. Corpus callosum (CC) and cavum septum pellucidum (CSP) abnormalities were the most frequent CNS abnormalities (47.1%, 8/17) with a diagnostic yield of 50%. A total of 29.4% (5/17) foetuses had variants of uncertain significance (VUS). Particularly, maternal uniparental disomy 16 and a <i>de novo</i> mosaic 4p12p11 duplication were simultaneously detected in one foetus with abnormal sulcus development. In addition, parentally inherited chromosomal inversions were identified in two foetuses. GS demonstrates its feasibility in providing genetic diagnosis for foetal CNS abnormalities and shows the potential to expand the application to foetuses with other ultrasound anomalies in prenatal diagnosis.

基因组测序（Genome Sequencing, GS，测序覆盖深度＞30×）的临床有效性已在产后临床场景中得到初步验证。本研究旨在探究三联体基因组测序（trio-Genome Sequencing, trio-GS）作为产前检测手段，用于诊断中枢神经系统（Central Nervous System, CNS）畸形的潜在应用价值。我们对17例中枢神经系统畸形胎儿组成的前瞻性队列实施了三联体基因组测序，对单核苷酸变异（Single Nucleotide Variation, SNV）、小片段插入缺失（Small Insertion and Deletion, Indel）、拷贝数变异（Copy Number Variation, CNV）、结构变异（Structural Variant, SV）以及杂合性缺失（Loss of Heterozygosity, AOH）进行分析，并依据美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics, ACMG）指南完成变异分类。三联体基因组测序在29.4%（5/17）的胎儿中检出了具有诊断意义的遗传学结果，致病变异分别见于*SON*、*L1CAM*、*KMT2D*及*ASPM*基因。胼胝体（Corpus Callosum, CC）与透明隔腔（Cavum Septum Pellucidum, CSP）畸形为最常见的中枢神经系统畸形（占比47.1%，8/17），其诊断检出率达50%。总计29.4%（5/17）的胎儿检出意义未明变异（Variants of Uncertain Significance, VUS）。尤为值得关注的是，1例脑沟发育异常的胎儿同时检出了16号染色体母源单亲二倍体以及新发（de novo）嵌合型4p12-p11片段重复。此外，本研究还在2例胎儿中检出了亲本遗传性染色体倒位。本研究证实，基因组测序可为胎儿中枢神经系统畸形提供遗传学诊断，具备临床可行性，同时也显示出其有望将应用范围拓展至产前诊断中存在其他超声异常的胎儿群体。