不明原因散发性全面发育迟缓儿童遗传因素预测表的制订及临床应用

Development and clinical application of a genetic risk scale for children with sporadic unexplained global developmental delay

摘要:

目的 通过分析散发性不明原因全面发育迟缓（GDD）患儿的临床特征，制订该类患儿的遗传因素风险预测表，以助于筛选需要进一步进行遗传学检测的患儿，缩短病因学诊断流程。方法 选取2019年6月—2022年6月在赣州市妇幼保健院儿童神经康复科就诊的散发性不明原因GDD患儿396例。依据基因测序结果将检测结果阳性的患儿归为阳性组（130例），检测结果阴性的患儿归为阴性组（266例）。通过回顾性分析25项临床特征的组间差异，制订遗传因素风险预测表，并使用受试者工作特征（ROC）曲线评估该量表预测患儿基因诊断阳性率的效能。结果 阳性组与阴性组患儿父亲高龄生育、MRI提示结构畸形、癫痫、毛发异常、头围异常、颅骨外观异常、皮肤异常、眼外观异常或畸形、鼻梁外观异常或畸形、耳廓畸形或耳位异常、下颌畸形、牙齿异常、出生低张力、非智力因素合并症比较，差异均有统计学意义（P <0.05），依据综合筛选，将19个条目归类至双亲因素、异常面容、器官畸形、非智力因素合并症、异常头颅MRI改变5个项目作为最终量表条目，制订遗传因素风险预测表。ROC曲线结果提示量表曲线下面积为0.707，最佳截断值为3分，敏感性为60.8%（95% CI：0.518，0.691），特异性为75.6%（95% CI：0.699，0.805）。结论 不明原因GDD儿童遗传因素风险预测表可以根据临床特征预测不明原因GDD儿童基因检测结果的阳性概率，加快病因学诊断流程，为后续诊疗决策提供参考，具有临床应用价值。

Abstract:

Objective To analyze the clinical characteristics of children with sporadic unexplained global developmental delay (GDD) and to develop a genetic risk scale to assist in screening cases requiring further genetic tests to facilitate the process of etiological diagnosis.Methods This study analyzed 396 children with sporadic unexplained GDD in the Department of Pediatric Neurological Rehabilitation of Ganzhou Maternal and Child Health Care Hospital from June 2019 to June 2022. According to the results of gene sequencing, 130 children were included in the positive group and 266 children were included in the control group. Through retrospective analysis of 25 clinical characteristics between the groups, a genetic risk scale was developed. The receiver operating characteristic (ROC) curve was used to evaluate the efficacy of the scale in predicting the positive rate of genetic diagnosis in children.Results The two groups differed in clinical features including advanced paternal age, fetal abnormalities on MRI, epilepsy, paratrichosis, abnormal head circumference, abnormal appearance of the skull, abnormal skin, abnormal appearance or malformation of the eye, abnormal appearance or malformation of the nasal bridge, malformation of the auricle or abnormal ear position, malformation of the lower jaw, dental abnormalities, hypotonia at birth and non-intellectual disability (P < 0.05). Based on comprehensive analysis, 19 items involving parental factors, abnormal facial features, organ malformations, non-intellectual disability, and skull abnormalities on MRI were eventually included to establish a genetic risk scale. The ROC curve analysis revealed that the area under the curve (AUC) of the scale for predicting positive findings in genetic tests was 0.707, with an optimal cutoff of 3 points, a sensitivity of 60.8% (95% CI: 0.518, 0.691), and a specificity of 75.6% (95% CI: 0.699, 0.805).Conclusions The genetic risk scale established in our study may predict the positive rate of the genetic tests for children with unexplained GDD based on clinical characteristics. It not only facilitates the process of etiological diagnosis but also provides a basis for subsequent decision-making of diagnosis and treatment, and therefore is of great value for being applied in clinical practice.