A Multi-Center Study: Developing a Nomogram for Predicting Genetic Results of Trio-Based Whole-Exome Sequencing...

The diagnostic efficacy of empirical trio-based whole-exome sequencing (trio-WES) for unexplained syndromic neurodevelopmental disorders (NDDs) remains unsatisfactory. This study aimed to explore the diagnostic value of phenotypic indicators and establish a nomogram for predicting the genetic results of trio-WES for diagnosing patients with unexplained s-NDDs.

We retrospectively collected phenotypic and genotypic data from 265 children with s-NDDs who received trio-WES at Sun Yat-sen Memorial Hospital (training cohort), 38 and 97s-NDDs patients with trio-WES test at Shenshan Medical Center (validation cohort-1) and Weierkang Children's Rehabilitation Center (validation cohort-2), respectively. Logistic analysis was employed to identify the independent predictors of a positive trio-WES diagnosis in the training cohort for model establishment. The predictive performance and robustness of the model were assessed using receiver operating characteristic (ROC) and confusion matrix analyses, respectively.

The analysis revealed that the severity of neurodevelopmental delays, head circumference abnormality, and complexity of neurodevelopmental comorbidities were independent predictive indicators for distinguishing s-NDDs patients with positive trio-WES results. The nomogram combining the three predictors showed good predictive performance with an area under the ROC (AUC) in the training cohort of 0.827 (95% CI: 0.775-0.879), yielding a confusion matrix with sensitivity, specificity, accuracy, precision, and F1 score of 78.23%, 78.01%, 78.11%, 75.78%, and 0.77, respectively. The model also had an excellent prediction in the external validation cohorts (AUC: 0.953; 95% CI: 0.881-0.998, sensitivity: 88.89%; specificity: 80.00%; accuracy: 84.21%; precision: 80.00%; and F1 score: 0.84 in validation cohort-1 and AUC: 0.910; 95% CI: 0.843-0.978, sensitivity: 83.33%; specificity: 85.45%; accuracy: 84.54%; precision: 81.40%; and F1 score: 0.82 in validation cohort-2).

The model can serve as a useful tool for assisting decision-making in applying trio-WES in the diagnostic strategy for s-NDDs, helping to implement personalized pre-diagnosis assessments for affected families.