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BackgroundThe molecular basis of heterotaxy and congenital heart malformations associated with disruption of left–right asymmetry is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far.ObjectiveWe sought to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab–Muslim descent, using next-generation sequencing techniques.MethodsDetailed clinical phenotyping followed by whole-exome sequencing (WES) was pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families.ResultsUsing WES, we reached a molecular diagnosis for 17 of the 30 probands (56.7%). Genes known to be associated with heterotaxy and/or primary ciliary dyskinesia, in which homozygous pathogenic or likely pathogenic variants were detected, included CFAP53 (CCDC11), CFAP298 (C21orf59), CFAP300, LRRC6, GDF1, DNAAF1, DNAH5, CCDC39, CCDC40, PKD1L1 and TTC25. Additionally, we detected a homozygous disease causing mutation in DAND5, as a novel recessive monogenic cause for heterotaxy in humans. Three additional probands were found to harbour variants of uncertain significance. These included variants in DNAH6, HYDIN, CELSR1 and CFAP46.ConclusionsOur findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next-generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families.

Major perioperative cardiovascular events are important causes of morbidity in pediatric patients with congenital heart disease who undergo reparative surgery. Current preoperative clinical risk assessment strategies have poor accuracy for identifying patients who will sustain adverse events following heart surgery. There is an ongoing need to integrate clinical variables with novel technology and biomarkers to accurately predict outcome following pediatric heart surgery. We tested whether preoperative levels of miRNAs-208a can serve as such a biomarker. Serum samples were obtained from pediatric patients immediately before heart surgery. MiRNA-208a was quantified by RQ-PCR. Correlations between the patient's clinical variables and miRNA levels were tested. Lower levels of preoperative miRNA-208a correlated with and could predict the appearance of postoperative cardiac and inflammatory complications. MiRNA-208a may serve as a biomarker for the prediction of patients who are at risk to develop complications following surgery for the repair of congenital heart defects.

Viral myocarditis (VM) can be a life-threatening event resulting in cardiac failure, chronic cardiomyopathy, and death. VM typically includes three phases, i.e., acute, subacute, and resolution/chronic. We prospectively investigated cardiac- and inflammatory-associated plasma-circulating miRNA levels in eight pediatric patients with VM during the three stages of the disease. The level of cardiac-associated miR-208a was significantly elevated during the acute phase compared with the subacute and resolution/chronic phases. The level of cardiac- and inflammatory-associated miR-21 was significantly elevated during the acute phase compared to the resolution/chronic phase. Moreover, cardiac-associated miR-208b levels during the subacute phase correlated with systolic left ventricular function recovery as measured during the resolution/chronic phase. The findings of our study demonstrate an association between cardiac damage and the inflammatory response and the expression of miR-208a and miR-21 during the pathological progression of myocarditis. We also found that miR-208b levels exhibit a prognostic significance for left ventricular functional recovery.

Current clinical risk assessment strategies have poor accuracy for identifying patients who will suffer adverse perioperative events. There is an ongoing need to integrate clinical variables with novel technology and biomarkers to accurately predict outcome after pediatric heart surgery. We tested the hypothesis that miRNAs-208a, -208b, and -499 can serve as noninvasive biomarkers for the extent of myocardial damage and the postoperative clinical course of pediatric patients with congenital heart defects (CHDs) at an early time point following surgery. Serum samples were obtained from 79 pediatric patients before and 6, 12, and 24 h after surgery. MiRNAs-208a, -208b, and -499 were quantified by RQ-PCR. Correlations between the patient's clinical variables and miRNA levels were tested. Our results show that the levels of the three miRNAs were elevated at 6 h after surgery, remained high at 12 h and declined at 24 h after the operation. The amount of all three miRNAs at 6 h after surgery correlated with surgical and laboratory parameters. Their amount at 12 h after surgery correlated with the length of stay at the hospital. Expression levels of miRNA-208a at 6 h were related to the appearance of cardiac complications, and could predict whether a patient will sustain complications or will be ventilated for more than 48 h after surgery. Circulating miRNA-208a is a predictor for the risk of developing cardiac complications during the postoperative course as early as 6 h after heart surgery for CHD in pediatric patients.

Pulmonary arterial thrombosis is an extremely rare occurrence in the neonatal population. We describe a 2-week-old female neonate who presented in critical condition with severe cyanosis and dehydration and was found to have a large thrombus in the main branches of the pulmonary arteries. She was successfully treated with surgical embolectomy. Pulmonary arterial thrombosis should always be considered in the differential diagnosis of a dehydrated neonate presenting with severe cyanosis and evidence of pulmonary hypertension.

Background Excessive hemorrhage is a major complication after cardiac surgery requiring cardiopulmonary bypass (CPB). The aim of this study was to define the potential role of the cone and platelet analyzer (CPA) and the rotating thromboelastogram (ROTEM) point of care tests in children undergoing CPB. Procedure We prospectively studied 15 pediatric patients aged 1 month to 10 years. Blood count, blood coagulation tests (prothrombin time [PT], activated partial thromboplastin time, fibrinogen, thrombin time), CPA and ROTEM parameters were measured before and after CPB. Demographic and surgical data were recorded as were those on perioperative blood loss and blood product transfusion. Results Low body weight, longer duration on CPB and lower core body temperature were associated with an increased bleeding risk. The ROTEM test showed a significant prolongation of clotting time and decreased maximal clot firmness (MCF) postoperatively in children with increased bleeding. The coagulation parameters associated with increased bleeding were: prolonged PT, lower fibrinogen levels, prior to surgery, and lower MCF after surgery. CPA test findings were not associated with postoperative bleeding in our patients. Conclusions CPA did not serve as a prognostic tool for predicting bleeding risk in children undergoing CPB. The change in ROTEM's post-CPB results associated with bleeding tendency, and they may predict for poorer clot formation and stability. Pediatr Blood Cancer 2011;56:794–798. © 2010 Wiley-Liss, Inc.

Down syndrome (DS), or trisomy 21, is a common disorder associated with several complex clinical phenotypes. Although several hypotheses have been put forward, it is unclear as to whether particular gene loci on chromosome 21 (HSA21) are sufficient to cause DS and its associated features. Here we present a high-resolution genetic map of DS phenotypes based on an analysis of 30 subjects carrying rare segmental trisomies of various regions of HSA21. By using state-of-the-art genomics technologies we mapped segmental trisomies at exon-level resolution and identified discrete regions of 1.8–16.3 Mb likely to be involved in the development of 8 DS phenotypes, 4 of which are congenital malformations, including acute megakaryocytic leukemia, transient myeloproliferative disorder, Hirschsprung disease, duodenal stenosis, imperforate anus, severe mental retardation, DS-Alzheimer Disease, and DS-specific congenital heart disease (DSCHD). Our DS-phenotypic maps located DSCHD to a DSCR1 and DYRK1A , or APP , in causing several severe DS phenotypes. Our study demonstrates the value of combining advanced genomics with cohorts of rare patients for studying DS, a prototype for the role of copy-number variation in complex disease.