2 Structured abstractBackground: Tetralogy of Fallot (TOF), the most frequent cyanotic congenital heart disease, is associated with a wide range of intra-and extracardiac phenotypes. In order to get further insight into genotype-phenotype correlation we comprehensively investigated a large cohort of 230 unselected patients with TOF. Methods and Results:We studied 230 patients with TOF by karyotyping, comprehensive 22q11.2 deletion testing and sequencing of TBX1, NKX2.5 and JAG1, as well as molecular karyotyping in selected patients. We found pathogenic genetic aberrations in 42 patients (18%), with 22q11.2 deletion as the most common diagnosis (7.4%), followed by trisomy 21 (5.2%) and other chromosomal aberrations or submicroscopic copy number changes (3%). Mutations in JAG1 were detected in three patients with Alagille syndrome (1.3%), while NKX2.5 mutations were seen in two patients with non-syndromic TOF (0.9%). One patient showed a recurrent polyalanine stretch elongation within TBX1 for which we show that this represents a true mutation resulting in loss of transcriptional activity due to cytoplasmatic protein aggregation. Conclusion: We show that 22q11.2 deletion represents the most common known cause of TOF and that the associated cardiac phenotype is distinct for obstruction of the proximal pulmonary artery, hypoplastic central pulmonary arteries and subclavian artery anomalies. Atrioventricular septal defect associated with TOF is very suggestive of trisomy 21 and almost excludes 22q11.2 deletion. We report a further patient with a recurrent polyalanine stretch elongation within TBX1 and for the first time link TBX1 cytoplasmatic protein aggregation to congenital heart defects.3 Abstract Tetralogy of Fallot (TOF), the most frequent cyanotic congenital heart disease, is associated with a wide range of intra-and extracardiac phenotypes. We investigated genotype-phenotype correlation in a large cohort of 230 unselected patients with TOF, in whom we performed karyotyping, comprehensive 22q11.2 deletion testing and sequencing of TBX1, NKX2.5 and JAG1, as well as molecular karyotyping in patients with TOF and otherwise unexplained mental retardation. We found pathogenic genetic aberrations in 42 patients (18%), with 22q11.2 deletion as the most common diagnosis (7.4%), followed by trisomy 21 (5.2%) and other chromosomal aberrations or submicroscopic copy number changes (3%). Mutations in JAG1 were detected in three patients with Alagille syndrome (1.3%), while NKX2.5 mutations were seen in two patients with non-syndromic TOF (0.9%). One patient showed a polyalanine stretch elongation within TBX1 which was previously reported as variant of unknown significance in a patient with isolated interruption of the aortic arch. We show that this represents a true mutation resulting in loss of transcriptional activity due to cytoplasmatic protein aggregation, for the first time linking the latter to congenital heart defects. The cardiac anomalies of this patient fit into the spectrum of 22q11.2 deletion, and were distin...

Objective-To investigate the specific sequelae of the Fontan operation, and particularly the potential sequelae of chronically elevated systemic venous pressure. Design-A retrospective analysis of clinical and haemodynamic data and evaluation of organ function in 80 surviving patients undergoing modified Fontan operation for various forms of underlying functionally univentricular hearts. Patients-65 patients (81%) who had undergone a total cavopulmonary anastomosis and 15 an atriopulmonary anastomosis. Follow up ranged from 12 to 106 months (mean 54 (SD 23) months). Results-62 patients underwent postoperative cardiac catheterisation (mean systemic venous pressure 10-5 (2.5) mm Hg and cardiac index 3-1 (0.7) 1lmin/m2). Older age at operation was significantly correlated with both higher systemic venous pressure and lower cardiac index. Atrial arrhythmia was documented on Holter electrocardiogram in 17%. Protein losing enteropathy (with abnormal a,-antitrypsin clearance) was found in 2/80 patients (2.5%). Ten patients had hypoproteinaemia, with a significantly higher incidence in patients after total cavopulmonary anastomosis and young age at operation. Liver function tests reflecting liver synthesis and metabolism were normal in all, whereas mild cholestasis was found in nearly 300/o-predominantly in patients with a cardiac index of < 3 I/min/m2 (P = 0 045). Five patients (6.2%) developed atrial thrombosis. Coagulation factor analysis in 44 patients showed protein C deficiency in 11 (25%); laboratory signs of activation of the coagulation system were found in four of these (9%). None of the abnormal laboratory indices was significantly related to underlying cardiac malformation, postoperative systemic venous pressure, or follow up interval.Conclusions-A high proportion of clinically asymptomatic patients had abnormal laboratory findings on mid-term follow up. Detailed evaluation of organ function is necessary to detect the need for further diagnostic procedures before clinical symptoms develop. (Heart 1997;78:154-159)

A prophylactic anticoagulation strategy that considers the surgical technique and potential predisposing circumstances proved effective in the prevention of late thrombotic complications after total cavopulmonary anastomosis. There is no need for routine anticoagulation during long-term follow-up after Fontan-type surgery in pediatric patients.

In patients with conotruncal malformations, anomalies of the subclavian arteries are the most important anatomical marker for the presence of monosomy 22q11.2, independent of the laterality of the aortic arch. Therefore, we recommend cytogenetic testing for this microdeletion in all patients with subclavian artery anomalies and conotruncal malformations.

In a high proportion of hearts with complex univentricular anatomy, associated anomalies, and borderline hemodynamics, the Fontan operation can be performed as a total cavopulmonary anastomosis with acceptable intermediate postoperative morbidity and hemodynamic results.