Wu Dandan, Chen Ran, Zhang Jerry, Yan Wu, Chen Mengyin, Xia Dongqing, Li Xiaonan, Dai Yanyan, Chen Yinhua, Li Rong
Child Mental Health Deparment, Children's Hospital of Nanjing Medical University, NanjingJiangsu, 210008, China.
Child Healthcare Department, Children's Hospital of Nanjing Medical University, Jiangdong South No.8 Road, Nanjing, Jiangsu, 210008, China.
Ital J Pediatr. 2025 Jan 23;51(1):9. doi: 10.1186/s13052-025-01839-6.
This study aimed to investigate deoxyribonucleic acid (DNA) copy number variations (CNVs) in children with neurodevelopmental disorders and their association with craniofacial abnormalities.
A total of 1,457 children who visited the Child Health Department of our hospital for unexplained Neurodevelopmental disorders (NDDs) between November 2019 and December 2022 were enrolled. Peripheral venous blood samples (2 mL) were collected from the children and their parents for whole-exome sequencing. Positive results were verified through Sanger sequencing for locus and pedigree validation. Simultaneously, a specific sign-scoring scale was created to evaluate characteristics related to the developments of eyes, nose, ears, eyebrows, head, mouth, face, trunk, limbs, and reproductive, urinary, and cardiovascular systems.
A total of 536 children (36.78%, 536/1,457) were found to have genetic variations, with 379 (70.71%, 379/536) exhibiting pathogenic monogenic mutations. Furthermore, 157 children (29.29%, 157/536) harbored DNA copy number variants, encompassing microdeletions (68.15%, 107/157) and microduplications (31.85%, 50/157). Regarding the pathogenicity of CNVs, 91 (57.96%, 91/157) were identified as pathogenic, 28 (17.83%, 28/157) as variants of uncertain clinical significance (VOUS), and 38 (24.20%, 38/157) as benign according to the American College of Medical Genetics and Genomics (ACMG).Using a specific sign-scoring scale, the proportion of pathogenic CNVs in children graded 1 point or higher (64%, 58/91) was significantly higher than that of non-pathogenic CNVs (43%, 29/66) (P < 0.05). Furthermore, the proportion of microdeletions in children graded 1 point or higher (60.75%, 65/107) was significantly higher than those carrying microduplications (44%, 22/50) (P < 0.05). The proportion of pathogenic microdeletions in children graded 1 point or higher (73.43%,47/64) was significantly higher than those carrying pathogenic microduplications (40.74%, 11/27) (P < 0.05).
The positive rate of whole-exome sequencing for children with combined craniofacial abnormalities and NDDs exceeds the international average in our study cohort. Thus, whole-exome sequencing may be recommended for precise diagnosis of neurogenetic diseases in such cases.
本研究旨在调查神经发育障碍儿童的脱氧核糖核酸（DNA）拷贝数变异（CNV）及其与颅面异常的关联。
纳入2019年11月至2022年12月期间因不明原因的神经发育障碍（NDD）前来我院儿童健康科就诊的1457名儿童。采集儿童及其父母的外周静脉血样本（2毫升）进行全外显子测序。通过桑格测序对阳性结果进行验证，以进行位点和家系验证。同时，创建了一个特定的体征评分量表，以评估与眼睛、鼻子、耳朵、眉毛、头部、嘴巴、面部、躯干、四肢以及生殖、泌尿和心血管系统发育相关的特征。
共发现536名儿童（36.78%，536/1457）存在基因变异，其中379名（70.71%，379/536）表现为致病性单基因突变。此外，157名儿童（29.29%，157/536）存在DNA拷贝数变异，包括微缺失（68.15%，107/157）和微重复（31.85%，50/157）。根据美国医学遗传学与基因组学学会（ACMG）的标准，在CNV的致病性方面，91名（57.96%，91/157）被鉴定为致病性，28名（17.83%，28/157）为临床意义未明的变异（VOUS），38名（24.20%，38/157）为良性。使用特定的体征评分量表，评分1分及以上的儿童中致病性CNV的比例（64%，58/91）显著高于非致病性CNV的比例（43%，29/66）（P<0.05）。此外，评分1分及以上的儿童中微缺失的比例（60.75%，65/107）显著高于携带微重复的儿童（44%，22/50）（P<0.05）。评分1分及以上的儿童中致病性微缺失的比例（73.43%，47/64）显著高于携带致病性微重复的儿童（40.74%，11/27）（P<0.05）。
在我们的研究队列中，合并颅面异常和NDD的儿童全外显子测序阳性率超过国际平均水平。因此，对于此类病例，建议进行全外显子测序以精确诊断神经遗传疾病。
