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
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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.
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