30: Bi‑allelic POPDC2 variants and a recessive cardiac conduction syndrome

Nicastro M et al., The American Journal of Human Genetics - Researchers identify bi-allelic POPDC2 variants in multiple families causing sinus-node dysfunction, atrioventricular conduction defects and, in some cases, hypertrophic cardiomyopathy, and investigate structural, electrophysiological and population-level evidence for pathogenicity. Key terms: POPDC2, cardiac conduction, TREK-1, cAMP binding, hypertrophic cardiomyopathy.

Study Highlights:
Bi-allelic POPDC2 variants were found in four unrelated families and associated with sinus node disease, AV conduction defects and HCM. Homology models predict impaired cAMP binding by POPDC2 variants and electrophysiology shows mutant POPDC2 fails to increase TREK-1 current density. Muscle biopsy and transcriptomics place POPDC1/POPDC2 dysfunction in conduction-system cells, and population analyses of >1 million individuals indicate heterozygous carriers are unlikely to develop clinical disease. Together the data support POPDC2 loss-of-function as a recessive cardiac syndrome gene.

Conclusion:
Bi-allelic loss-of-function POPDC2 variants cause an autosomal recessive cardiac syndrome marked by conduction disease and occasional hypertrophic cardiomyopathy, likely via impaired cAMP-dependent regulation of TREK-1 and disrupted POPDC1/2 stability or trafficking.

QC:
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Metadata checks passed: 4.
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QC result: Pass.

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Article title:
Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy

First author:
Nicastro M

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2025.04.016

Reference:
Nicastro M, Vermeer AMC, Postema PG, et al. Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy. The American Journal of Human Genetics. 2025;112:1–18. doi:10.1016/j.ajhg.2025.04.016

License:
CC BY

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