Rare and Common Variants Uncover the Role of the Atria in Coarctation of the Aorta

Figures

• 

  Figure 1. Rare pathogenic MYH6 variants enriched in LVOTO cohort. (A) Pathogenic MYH6 variants identified in Pittsburgh cohort. Variants R721Q and A1753T (with black box) were found in the same patient. The Icelandic R721W variant is indicated with a star. (B) Burden analysis yielded odds ratio indicating significant excess of rare pathogenic MYH6 variants associated with CoA and other related LVOTO. p values were obtained by Fisher’s exact test. 95% CI: 95% confidence interval. (C) Proportion of subjects with PCDHA delCNVs (16.8 kb/13.6 kb) and/or pathogenic MYH6 variants among LVOTO in Pittsburgh cohort.

• 

  Figure 2. Atrial specific expression of MYH6 and the PCDHA gene cluster. (A) Spatial transcriptomic heatmap revealed abundant MYH6 expression predominantly in the atria of embryonic heart at 4.5–5, 6.5 and 9 postconceptional weeks (PCW). Heart regions color coded as shown. CVM: compact ventricular myocardium. TVM: trabecular ventricular myocardium. AM: atrial myocardium. OFT: outflow tract/large vessels. AVM&V: atrioventricular mesenchyme & valves. MM &V: mediastinal mesenchyme & vessels. CB & IC: cavities with blood and immune cells. EP: epicardium. (B) Atria = expression of Myh6 and Pcdha gene cluster in mouse embryonic heart. Dot size shows proportion of cells expressing Pcdha (Exp%). Color denotes average expression (Ave). A, atrium; V, ventricle; RA, right atrium; LA, left atrium; AVC, atrioventricular canal; RV, right ventricle; RS, right ventricular septum; LS, left ventricular septum; LV, left ventricle; OFT, outflow tract; PO, proximal outflow tract; DO, distal outflow tract.

• 

  Figure 3. cis-eQTL analysis of PCDHA delCNV impact on PCDHA gene expression. (A) GTEx database showed in the atria, three tagSNPs among top 5 cis-eQTLs were associated with significant change in PCDHA10 expression. (B) eQTL obtained using GTEx data showed reduced expression of PCDHA10 associated with the 16.8 kb PCDHA delCNV tracked by rs7702020 (A/G, non-risk/risk allele). p-values adjusted to the β distribution. (C) Volcano plot shows cis-eQTL tracked expression of the PCDHA cluster in different human tissue via rs77020201 for the 16.8 kb PCDHA delCNV. Negative/positive slope indicates decrease/increase expression respectively. Grey dots denote nonsignificant cis-eQTL associations.

• 

  Figure 4. Atrial vs. ventricular hemodynamic model of coarctation. MYH6 and PCDHA are both expressed predominantly in the atria during early human and mouse embryonic development. Ventricular model of coarctation (CoA) (A) proposes that flow provided by ventricular contractile force plays a predominant role in the developmental etiology of CoA (A). In contrast, in the atrial model of CoA (B), flow provided by atrial contraction plays a predominant role in the developmental etiology of CoA. Diagrams adapted with permission from van Eif et al. (2018) [32]. RA, right atrium; LA, left atrium; AVC, atrioventricular canal; RV, right ventricle; LV, left ventricle; OFT, outflow tract.