Abstract：
Exome sequencing (ES) has emerged as an essential tool in the evaluation of neurodevelopmental disorders (NDD) of unknown etiology. Genome sequencing (GS) offers advantages over ES due to improved detection of structural, copy number, repeat number and non-coding variants. However, GS is less commonly utilized due to higher cost and more intense analysis. Here, we present nine cases of pediatric NDD that were molecularly diagnosed with GS between 2017 and 2022, following non-diagnostic ES. All individuals presented with global developmental delay or regression. Other features present in our cohort included epilepsy, white matter abnormalities, brain malformation and dysmorphic features. Two cases were diagnosed on GS due to newly described gene-disease relationship or variant reclassification (MAPK8IP3, CHD3). Additional features missed on ES that were later detected on GS were: intermediate-size deletions in three cases who underwent ES that were not validated for CNV detection, pathogenic variants within the non-protein coding genes SNORD118 and RNU7-1, pathogenic variant within the promoter region of GJB1, and a coding pathogenic variant within BCAP31 which was not sufficiently covered on ES. GS following non-diagnostic ES led to the identification of pathogenic variants in this cohort of nine cases, four of which would not have been identified by reanalysis alone.
摘要：
外显子组测序（ES）已成为评估病因不明的神经发育障碍（NDD）的重要工具。基因组测序（GS）具有优于ES的优势，因为它可以改善对结构的检测，副本编号,重复编号和非编码变体。然而,由于更高的成本和更强烈的分析，GS不太常用。这里,我们介绍了2017年至2022年间非诊断性ES后分子诊断为GS的9例小儿NDD病例.所有个体均出现整体发育迟缓或退化。我们队列中的其他特征包括癫痫，白质异常，脑畸形和畸形特征。由于新描述的基因-疾病关系或变异重新分类（MAPK8IP3，CHD3），在GS上诊断出2例。后来在GS上检测到的ES上遗漏的其他特征是：在三个未进行CNV检测验证的ES患者中，中等大小的缺失。非蛋白质编码基因SNORD118和RNU7-1内的致病性变异体,GJB1启动子区域内的致病性变异体,以及ES上未充分覆盖的BCAP31内的编码致病性变异体.非诊断性ES后的GS导致在9例病例队列中鉴定出致病变异，仅通过重新分析就无法确定其中四个。
