Abstract：
Genome sequencing (GS) has been used in the diagnosis of global developmental delay (GDD)/intellectual disability (ID). However, the performance of GS in patients with inconclusive results from chromosomal microarray analysis (CMA) and exome sequencing (ES) is unknown. We recruited 100 pediatric GDD/ID patients from multiple sites in China from February 2018 to August 2020 for GS. Patients have received at least one genomic diagnostic test before enrollment. Reanalysis of their CMA/ES data was performed. The yield of GS was calculated and explanations for missed diagnoses by CMA/ES were investigated. Clinical utility was assessed by interviewing the parents by phone. The overall diagnostic yield of GS was 21%. Seven cases could have been solved with reanalysis of ES data. Thirteen families were missed by previous CMA/ES due to improper methodology. Two remained unsolved after ES reanalysis due to complex variants missed by ES, and a CNV in untranslated regions. Follow-up of the diagnosed families revealed that nine families experienced changes in clinical management, including identification of targeted treatments, cessation of unnecessary treatment, and considerations for family planning. GS demonstrated high diagnostic yield and clinical utility in this undiagnosed GDD/ID cohort, detecting a wide range of variant types of different sizes in a single workflow.
摘要：
基因组测序（GS）已用于诊断全球发育迟缓（GDD）/智力障碍（ID）。然而,在染色体微阵列分析(CMA)和外显子组测序(ES)结果不确定的患者中,GS的表现尚不清楚.从2018年2月至2020年8月，我们从中国多个地点招募了100名儿童GDD/ID患者。患者在登记之前已经接受了至少一种基因组诊断测试。对其CMA/ES数据进行再分析。计算GS的产量，并研究CMA/ES漏诊的解释。通过电话采访父母来评估临床效用。GS的总诊断率为21%。通过对ES数据的重新分析，可以解决7例病例。由于方法不当，以前的CMA/ES错过了13个家庭。由于ES错过了复杂的变体，在ES重新分析后仍有两个未解决，和非翻译区的CNV。对确诊家庭的随访显示，有9个家庭在临床管理方面发生了变化，包括识别靶向治疗，停止不必要的治疗，以及计划生育的考虑。GS在这个未诊断的GDD/ID队列中显示出高诊断率和临床实用性，在单个工作流程中检测各种不同大小的变体类型。
