Objective: To evaluate the utility of whole-exome sequencing (WES) in early diagnosis for children with language delay/disorder. Methods: Children with language delay/disorder who were admitted to the Department of Health Care, Children's Hospital Affiliated to the Capital Pediatric Institute from January 2019 to December 2020 were analyzed retrospectively. Based on informed consent, the peripheral blood of the children and their parents was collected for WES. Combining the clinical phenotypes of the children, the candidate variants, including single nucleotide variants (SNVs) and copy number variations (CNVs), were selected for validation and family segregation analysis using Sanger sequencing, real-time PCR or CNV-Seq. The pathogenicity of variants was evaluated based on ACMG guideline following with finial genetic diagnosis. Based on whether genetic diagnosis was achieved or not, 125 children with comprehensive examination of the Children Neuropsychological and Behavioral Scale(CNBS-R2016) were sub-grouped (positive/negative group), and the total scores and the detailed scores of five developmental sections (gross motor, fine motor, adaptive ability, language and social behavior ability) between two subgroups were compared. Results: A total of 165 children with language delay/disorder were recruited, including 109 males and 56 females. The ratio of boys to girls was 1.95∶1.The age of the children was (3.2±1.2) years old, the median age was 3.0 years. 45 children carry disease-related pathogenic/likely pathogenic variants, including 36 SNVs and 9 CNVs. The genetic diagnostic yield of this cohort was 27.3% (45/165). The inheritance analysis for core family members showed de novo variant accounted for 86% of genetic diagnosis (31/36). The positive diagnosis rate in girls was 45% (25/56), which was significantly higher than that in boys (18.3%, 20/109, χ²=12.171, P<0.05). There was no significant difference in the rate of positive diagnosis among all age groups (χ²=4.349, P>0.05). Interestingly, the scores of gross motors of positive group were significantly lower than that of negative group (61.5 vs. 69.4, t=-2.610, P<0.05). Otherwise, no significant difference was seen between two groups(t=-0.933, -1.298, -0.114, -0.214, all P>0.05). Conclusions: Language delay/disorder has complex genetic heterogeneity. WES has important application value in early etiological diagnosis for children with language delay/disorder.
目的： 评估全外显子测序技术（WES）对儿童语言发育迟缓/障碍的早期诊断价值。 方法： 回顾性研究。选取 2019年1月至2020年12月于首都儿科研究所附属儿童医院保健科就诊的语言发育迟缓/障碍患儿为研究对象。知情同意基础上采集患儿和父母外周血进行WES，结合患儿的临床表型筛选候选变异，包括单核苷酸突变（SNVs）和基因拷贝数变异（CNVs）。候选变异利用Sanger测序/real-time PCR/CNV-Seq完成验证和家系分离分析，最终根据美国医学遗传学与基因组学学会（ACMG）指南完成致病性评估和遗传诊断。对其中完成《儿童神经心理行为检查量表2016版》检查的125例患儿，以WES检测结果阳/阴性分组，采用t检验比较两组患儿总发育商、大运动、精细动作、适应能力、语言和社会行为能区的发育水平。 结果： 165例语言发育迟缓/障碍患儿完成WES检测，男女比例为1.95∶1，男童109例，女童56例，年龄（3.2±1.2）岁、中位数3.0岁，共检测出与疾病相关的致病性突变者45例，阳性诊断率为27.3%（45/165）。其中36例检测到的变异为SNVs，9例为CNVs。家系成员的变异来源检测显示新发突变在致病性基因变异中占比为86%（31/36）。女童的阳性诊断率45%（25/56），显著高于男童（18.3%、20/109，χ²=12.171，P<0.05）；各年龄段的阳性诊断率无显著差异（χ²=4.349，P>0.05）；WES检测阳性组患儿大运动发育商均值低于阴性组（61.5±15.39 vs. 69.4±14.36），差异有统计学意义（t=-2.610，P<0.05）；两组患儿在精细动作、适应能力、语言、社会行为能区发育商的差异无统计学意义（t=-0.933、-1.298、-0.114、-0.214，P均>0.05）。 结论： 语言发育迟缓/障碍具有复杂的遗传异质性，WES在全外显子层面对语言发育迟缓/障碍儿童的早期病因诊断具有重要价值。.