Coarctation of the aorta (
CoA) and bicuspid aortic valve (BAV) often cooccur and are genetically linked
congenital heart defects (CHD). While
CoA is thought to have a hemodynamic origin from
ventricular dysfunction, we provide evidence pointing to atrial hemodynamics based on investigating the genetic etiology of
CoA. Previous studies have shown a rare MYH6 variant in an Icelandic cohort, and two common deletions in the protocadherin α cluster (PCDHA delCNVs) are significantly associated with
CoA and BAV. Here, analysis of a non-Icelandic white CHD cohort (n = 166) recovered rare MYH6 variants in 10.9% of
CoA and 32.7% of BAV/
CoA patients, yielding odds ratios of 18.6 (p = 2.5 × 10-7) and 20.5 (p = 7.4 × 10-5) for the respective association of MYH6 variants with
CoA and BAV/
CoA. In combination with the PCHDA delCNVs, they accounted for a third of
CoA cases. Gene expression datasets for the human and mouse embryonic heart showed that both genes are predominantly expressed in the atria, not the ventricle. Moreover, cis-eQTLs analysis showed the PCHDA delCNV is associated with reduced atrial expression of PCHDA10, a gene in the delCNV interval. Together, these findings showed that PCDHA/MYH6 variants account for a substantial fraction of
CoA cases. An atrial rather than ventricular hemodynamic model for
CoA is indicated, consistent with the known early atrial functional dominance of the human embryonic heart.