The ostium secundum atrial septal defect (ASDII) is the most common type of congenital heart disease and is characterized by a left to right shunting of oxygenated blood caused by incomplete closure of the septum secundum. We identified a familial form of isolated ASDII that affects four individuals in a family of five and shows autosomal dominant inheritance. By whole genome sequencing, we discovered a new mutation (c.*1784T > C) in the 3′-untranslated region (3′UTR) of ACTC1, which encodes the predominant actin in the embryonic heart. Further analysis demonstrated that the c.*1784T > C mutation results in a new target site for miRNA-139-5p, a microRNA that is involved in cell migration, invasion, and proliferation. Functional analysis demonstrated that the c.*1784T > C mutation specifically downregulates gene expression in a luciferase assay. Additionally, miR-139-5p mimic causes further decrease, whereas miR-139-5p inhibitor can dramatically rescue the decline in gene expression caused by this mutation. These findings suggest that the familial ASDII may be a result of an ACTC1 3′UTR gain-of-function mutation caused by the introduction of a new miR-139-5p target site. Our results provide the first evidence of a pathogenic mutation in the ACTC1 3′UTR that may be associated with familial isolated ASDII.
Background: Prediction of in-hospital death is important for patient management as well as risk-adjusted evaluation of Congenital heart disease (CHD) surgery performance. Using a large database containing CHD surgery records of 12 years, we aim to establish patient-level in-hospital mortality prediction models.Methods: Patients with congenital heart disease who underwent surgery at Shanghai Children’s Medical Center from January 1, 2006, to December 31, 2017 were included in the study. Each procedure was assigned a complexity score based on Aristotle Score with modification. In-hospital mortalities for various surgery procedures were estimated. In-hospital death prediction models including a procedure complexity score and patient-level risk factors were constructed using logistic regression analysis and machine learning methods. The predictive values of the models were tested. Results: Among 24,684 patients underwent CHD operations, there were 595 (2.4%) in-hospital deaths. The results showed that AUC of the prediction model based on logistic regression is 0.864 (95% CI: 0.833-0.895, P <0.001), the sensitivity is 0.831 and the specificity is 0.786. The AUC of the Gradient boosting model is 0.884 (95 %% CI: 0.858-0.909, P <0.001), the sensitivity and specificity were 0.838 and 0.785 respectively. The feature importance analysis found that the variable (average score) that had the greatest impact on the model's prediction performance was operation score (95.6), and other variables (average scores) were Age (days) (95.5), Ultrasound MV (54.6), Ultrasound atrial level (54.5), Palliative operation (45.8), Operation history (38.8), Ultrasound TV2 (32.1), Urgent operation (30.8), Ultrasound ventricular level (30.5), and Spo2 ≤ 90% (30.3).Conclusions: Model constructed using machine learning method and logistic regression containing procedure complexity score and pre-operative patient-level factors had high accuracy in in-hospital mortality prediction. Operation score and age have the greatest impact on model prediction performance.
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