LAUSR

Wereadwith great interest the cohort studyof childrenwithepilepsy that was recently published by Zou et al. The authors recruited 320 paediatric epilepsy patients between October 2016 and December 2017 and performed genome sequencing on probands. They analysed genome sequencing data with comprehensive pedigree and clinical data and concluded that genome sequencing should be the first choice for genetic testing in epilepsy patients. We agree that the application of genome sequencing in children with epilepsy will lead to accurate interpretation of genetic testing and thus benefit therapeutic decision-making and precision medicine. However, there are severalmethodsand strategies to applyingnext-generation sequencing for clinical diagnostics, which vary in the type of sequencing regions and cost. According to the American College of Medical Genetics and Genomics guidelines, trio-based genetic analysis of the proband and both biological parents is important in determining if a variant is inherited or if it is de novo and thus affects variant classification and identification. Hence, our group retrospectively reviewed and analysedpaediatric epilepsy patientswhounderwent diagnostic trio-based clinical genetic testing at Shenzhen Children’s Hospital between September 2019 and June 2020. A total of 355 cases were included; 168 of the patients and their parents underwent wholeexome sequencing (WES), 48 patients and their parents underwent whole genome sequencing (WGS) and 139 patients underwent WGS while their parents underwentWES.We systematically reviewed detailed clinical records of patients in all groups.We evaluated the clinical characteristics that were associated with a positive genetic diagnosis and assessed the potential impact of the genetic diagnosis on management strategy. Zou’s group performed genome sequencing on 320 Chinese childrenwith epilepsy anduncovered pathogenic/likely pathogenic variants in 117 of the 320 children (36.6%). A similar diagnostic rate was observed in our analysis, with 117 of the 355 patients (32.96%) showing causative results (79 with single nucleotide variations or insertion deletions, 32 with copy number variations and five with mitochondrialmutations; Fig. 1A).We identified 89 causative single nucleotide variations or insertion deletion variants in 79 patients (Supplementary Table 1). The variants were most frequently found in PRRT2 (10/88, 11.36%), which is associated with benign familial infantile epilepsy, followed by SCN1A (7/88, 7.95%), which is associated with Dravet syndrome and TSC2 (5/88, 5.68%), which is associated with tuberous sclerosis. Interestingly, five patients were identified with multilocus disease-causing genomic variations, which may lead to multiple genetic diagnoses (Fig. 1B and Supplementary Tables 1 and 2). All patients with two molecular diagnoses showed two pathogenic variants that cause autosomal dominant disease, and three of themshowed two de novomutations in autosomal dominant disease genes. A 6-month-old boy (Case GT110) had a de novo missense mutation in SYNGAP1 and a 16p11.2 recurrent microdeletion (524.61 Kb) inherited from his mother. Another 4-month-old boy (Case GT130) had a de novo missense mutation in PACS1 and a recurrent frameshift mutation in PRRT2 inherited from his father, who experienced seizures as a