A research team at Amsterdam UMC’s Amsterdam Cardiovascular Sciences (ACS) has identified genetic variants in POPDC2 as a novel cause for a rare inherited cardiac condition involving cardiac conduction disease and hypertrophic cardiomyopathy. The study, led by pediatrician-in-training Dr. Najim Lahrouchi, connects clinical and genetic findings in patients to prior animal research, where disruption of POPDC2 caused similar cardiac abnormalities in mice and zebrafish.
Variants of POPDC2
Through an international collaboration, the team identified recessive POPDC2 variants in patients from four unrelated families with overlapping cardiac phenotypes presenting at young age. The phenotypic spectrum sonsists of sinus node dysfunction, AV conduction defects and hypertrophic cardiomyopathy. This effort enabled a comprehensive investigation of this rare but serious disorder.
POPDC2 gene
POPDC2 encodes a protein that regulates heart rhythm by modulating TREK-1 potassium channels via cAMP signaling. Modelling and electrophysiological studies suggest effects of identified POPDC2 variants on cAMP binding and TREK-1 current. Single-cell RNA sequencing in human hearts confirmed that POPDC2 is expressed in human cardiac conduction cells and cardiomyocytes.
Clinical manifestations
Importantly, population-wide genetic data from over one million individuals showed no associated disease in heterozygous carriers, suggesting that heterozygous family members are unlikely to develop clinical manifestations. ‘This discovery is the first to robustly link POPDC2 to human disease and paves the way for improved genetic diagnosis and better risk assessment in families.’ Says Najim Lahrouchi. Our findings provide evidence for biallelic variants in POPDC2 causing a Mendelian autosomal recessive cardiac syndrome.
Photo: Florian Braakman & Adobe stock