Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel–encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.

Introduction: Neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and lymphocyte‐to‐monocyte ratio (LMR) are emerging biomarkers for systemic inflammation and have been shown to predict morbidity and mortality for several diseases. However, lack of pediatric reference intervals (RIs) prevents their comprehensive use in patient care and medical research.Material and Methods: We calculated reference intervals and corresponding confidence intervals for NLR, PLR, and LMR from birth to 18 years using a data‐mining approach: We analyzed 232 746 blood counts from 60 685 patients performed during patient care and excluded patients with elevated C‐reactive protein and procalcitonin. Test results were separated according to age and sex, and the distribution of physiological ratios was estimated using an indirect approach (refineR). Additionally, we investigated the ratios’ diagnostic benefit for different inflammatory diseases (acute appendicitis, asthma, Bell's palsy, Henoch‐Schonlein purpura, and cystic fibrosis) using the newly obtained reference intervals.Results: We estimated age‐ and sex‐specific reference intervals from birth to adulthood for NLR, PLR, and LMR. Analyses in pediatric inflammatory diseases showed that PLR and LMR were poor markers to detect the examined inflammatory diseases, while NLR was significantly increased in patients with appendicitis and asthma.Conclusion: We provide pediatric reference intervals for NLR, PLR, and LMR to improve the interpretation of these biomarkers in children.

Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10 ^-10 , OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10 ^-5 ). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A , which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A . Genomic and functional data support a causal role of WNT5A at the locus.

Fontan patients with protein‐losing enteropathy (PLE) represent poor candidates for cardiac transplantation due to end‐organ injury and severely impaired clinical condition. Ventricular assist device (VAD) therapy has evolved as a promising bridge to transplant strategy improving quality of life and survival on the waiting list. However, VAD therapy for the Fontan circulation remains challenging. For Fontan patients with preserved ventricular function implantation of a right ventricular assist device (RVAD) has been described by Prêtre et al as bridge to transplant. We present the second case of RVAD support in a Fontan patient with PLE.

Background Increased central venous pressure is inherent in Fontan circulation but not strongly related to Fontan complication. Abnormalities of the lymphatic circulation may play a crucial role in early Fontan complications. Methods This was a retrospective, single-center study of patients undergoing Fontan operation from 2008 to 2015. The primary outcome was significant early Fontan complication defined as secondary in-hospital treatment due to peripheral edema, ascites, pleural effusions, protein-losing enteropathy, or plastic bronchitis. All patients received T2-weighted magnetic resonance images to assess abdominal and thoracic lymphatic perfusion pattern 6 months after Fontan completion with respect to localization, distribution, and extension of lymphatic perfusion pattern (type 1–4) and with application of an area score (0–12 points). Results Nine out of 42 patients developed early Fontan complication. Patients with complication had longer chest tube drainage (mean 28 [interquartile range [IQR]: 13–60] vs. 13 [IQR: 2–22] days, p = 0.01) and more often obstructions in the Fontan circuit 6 months after surgery (56 vs. 15%, p = 0.02). Twelve patients showed little or no abnormalities of lymphatic perfusion (lymphatic perfusion pattern type 1). Most frequently magnetic resonance imaging showed lymphatic congestion in the supraclavicular region (24/42 patients). Paramesenteric lymphatic congestion was observed in eight patients. Patients with early Fontan complications presented with higher lymphatic area score (6 [min–max: 2–10] vs. 2 [min–max: 0–8]), p = 0.001) and greater distribution and extension of thoracic lymphatic congestion (type 3–4: n = 5/9 vs. n = 1/33, p = 0.001). Conclusion Early Fontan complication is related to hemodynamic factors such as circuit obstruction and to the occurrence and extent of lymphatic congestion.

Coarctation of the aorta (CoA) accounts for 5-8% of all congenital heart defects. CoA can be detected in up to 20% of patients with Ullrich-Turner syndrome (UTS), in which a part or all of one of the X chromosomes is absent. The etiology of non-syndromic CoA is poorly understood. In the present work, we test the hypothesis that rare copy number variation (CNV) especially on the gonosomes, contribute to the etiology of non-syndromic CoA. We performed high-resolution genome-wide CNV analysis using the Affymetrix SNP 6.0 microarray platform for 70 individuals with sporadic CoA, 3 families with inherited CoA (n=13) and 605 controls. Our analysis comprised genome wide association, CNV burden and linkage. CNV was validated by multiplex ligation-dependent probe amplification. We identified a significant abundance of large (>100 kb) CNVs on the X chromosome in males with CoA (p=0.005). 11 out of 51 (~ 22%) male cases had these large CNVs. Association analysis in the sporadic cohort revealed 14 novel loci for CoA. The locus on 21q22.3 in the sporadic CoA cohort overlapped with a gene locus identified in all familial cases of CoA (candidate gene TRPM2). We identified one CNV locus within a locus with high multipoint LOD score from a linkage analysis of the familial cases (SEPT9); another locus overlapped with a region implicated in Kabuki syndrome. In the familial cases, we identified a total of 7 CNV loci that were exclusively present in cases but not in unaffected family members. Of all candidate loci identified, the TRPM2 locus was the most frequently implicated autosomal locus in sporadic and familial cases. However, the abundance of large CNVs on the X chromosome of affected males suggests that gonosomal aberrations are not only responsible for syndromic CoA but also involved in the development of sporadic and non-syndromic CoA and their male dominance.