Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.

Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD

Papillary fibroelastoma of the left atrium in a 3-year-old boy

A 3 year old boy presented with a cardiac murmur. Except for mildly impaired physical condition that was more likely due to asthmatic bronchitis, he was asymptomatic. Cardiac echocardiography disclosed a large tumor in the left atrium originating from the interatrial septum. The patient was immediately referred to surgery for excision of the tumor. Histological examination of the tumor showed a typical papillary fibroelastoma. The occurrence of a papillary fibroelastoma in a child is a rarity

Severe dilated cardiomyopathy as an unusual finding in a young infant with mucolipidosis type 2

A neonate presented with mucopolysaccharidosis-like phenotypic expression and typical signs of dysostosis multiplex but without urinary excretion of glycosaminoglycans. Investigations of lysosomal enzymes in cultured fibroblasts revealed a mucolipidosis type 2, known as I-cell disease. We describe the fatal course of the patient due to complications of an uncommon dilated cardiomyopathy in this rare disease and discuss the pathogenesis

Methaemoglobinaemia after cardiac catheterisation: a rare cause of cyanosis

Two young women had unexpected cyanosis a few hours after cardiac catheterisation for electrophysiological investigation. The first patient had atrioventricular septal defect, had undergone repeated surgical interventions, and was referred because of atrial flutter. The second patient had ablation of an accessory pathway in Wolff-Parkinson-White syndrome. Local anaesthesia was performed with 40 ml prilocaine 2%. Cyanosis with oxygen saturation of 85% developed in both patients a few hours after the electrophysiological investigation. The patients were transferred to the intensive care unit and for the first patient a considerable diagnostic effort was made to rule out morphological complication. Finally methaemoglobinaemia of 16.7% and 33.4%, respectively, was found. Cyanosis resolved within 24 hours and did not reappear. Underlying glucose-6-phosphate dehydrogenase deficiency and erythrocyte-methaemoglobin reductase deficiency were ruled out. Physicians should be aware of this rare side effect of local anaesthetics in patients with unexpected cyanosis

Rapid right ventricular pacing is an alternative to adenosine in catheter interventional procedures for congenital heart disease

Objective: To describe the use of rapid right ventricular pacing to facilitate balloon stability during balloon dilatation procedures for congenital heart disease. Setting: Tertiary paediatric cardiac centre. Design and patients: This was a prospective pilot study of 37 consecutive patients with congenital aortic stenosis undergoing elective balloon dilatation. If the first dilatation manoeuvre failed due to balloon displacement, rapid right ventricular pacing at a rate of 220 beats/min was performed during repeat balloon inflation. Interventions: Balloon aortic valvotomy and rapid right ventricular pacing. Main outcome measures: Balloon stability versus displacement during balloon dilatation and procedure related complications. Results: Initial balloon displacement occurred and rapid right ventricular pacing was performed in 14 patients. The balloon remained in stable position in 11 patients. In three patients the balloon was displaced. In two of them an increase of the pacing rate to 240 beats/min provided balloon stability. In one patient stability was obtained at an unchanged pacing rate after correction of a suboptimal balloon position. No sustained arrhythmias occurred. There were no other procedure related complications. Conclusions: Rapid right ventricular pacing is a safe and effective method to provide balloon stability during balloon dilatation of the aortic valve. It may be applied in other fields of catheter intervention where it is desirable to maintain stable device positions during the critical phase of the procedure

Interventional closure of atrial septal defects with the Solysafe Septal Occluder - Preliminary results in children

BACKGROUND: To report usability, safety, and efficacy of the self-centering Solysafe Septal Occluder for transcatheter closure of secundum type atrial septal defect (ASD) in paediatric patients. METHODS: Retrospective observational clinical study in two tertiary care centers for congenital heart diseases. Patients: First 37 (median age 8.7 years, 68% female) consecutive patients with an ASD stretched diameter up to 22 mm in whom a Solysafe Septal Occluder was used to close a haemodynamically significant ASD. Interventions: Transcatheter closure of ASD was performed under general anaesthesia with trans-esophageal echo guidance. Stretched diameter of the ASD was assessed by balloon sizing. Main outcome measures: Rate of success, complete closure rate, and complications (defined as vascular complications, device-related complications such as embolism, thrombus formation, device erosions, infections, and arrhythmia) during follow up. RESULTS: 37 procedures were performed, success rate was 87% (32 of 37 pts.). A missing retroaortic rim was the main reason for device failure. Complete ASD closure rate was 78% immediately in cath lab (25 of 32 pts.), 90% after four weeks (28 of 31 pts.), 94% after three months (29 of 31 pts.), and 100% after six months (20 of 20 pts.). Procedure-related complication was femoral vein thrombosis in one patient. CONCLUSIONS: The Solysafe Septal Occluder is a feasible, safe, and clinically efficient new device for interventional closure of small to medium sized ASDs less than 23 mm stretched diameter in childhood. Limitations for the Solysafe device are ASDs with absent retroaortic rims and very small children with a body weight <10 kg