Episode 30: Heart in the Genes — A New Genetic Syndrome Linked to POPDC2

🫀 In this episode of Base by Base, we delve into a groundbreaking study by Nicastro et al. (2025), published in The American Journal of Human Genetics, which identifies bi-allelic variants in the POPDC2 gene as the cause of a novel autosomal recessive cardiac syndrome. This condition manifests with sinus node dysfunction, atrioventricular (AV) block, and in some cases, hypertrophic cardiomyopathy (HCM).

🔍 Study highlights:
The research demonstrates that pathogenic variants in POPDC2 disrupt its ability to bind cyclic AMP (cAMP), compromising its interaction with the TREK-1 potassium channel and affecting cardiac electrical activity.
Through in vitro electrophysiology, mutant POPDC2 variants failed to enhance TREK-1 current density, unlike the wild-type protein.
Structural modeling showed that disease-causing mutations cluster around key functional domains critical for cAMP binding and dimerization.
Muscle biopsy from an affected individual revealed a marked reduction in both POPDC2 and POPDC1 proteins, suggesting destabilization of their membrane complex.
Single-cell and spatial transcriptomics confirmed that POPDC2 is highly expressed in specialized cardiac conduction tissues—especially in the AV node and bundle cells—where it often co-localizes with POPDC1.
Large-scale population data (>1 million individuals) showed that heterozygous carriers of these rare variants do not display the disease phenotype, indicating a recessive inheritance pattern without clinical penetrance in carriers.

🧠 Conclusion:
This study establishes POPDC2 as a new Mendelian gene responsible for a previously unrecognized cardiac syndrome. It emphasizes the importance of functional genomics and integrative modeling to unravel complex genotype–phenotype relationships in cardiogenetics. These findings expand our understanding of the molecular mechanisms underlying cardiac conduction disorders and have important implications for genetic counseling and early diagnosis in affected families.

📖 Reference:
Nicastro, M., Vermeer, A.M.C., Postema, P.G., et al. (2025). Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy. The American Journal of Human Genetics, 112, 1–18. https://doi.org/10.1016/j.ajhg.2025.04.016

📜 License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/