36: Bi-allelic POPDC2 variants and a recessive cardiac syndrome

Nicastro M et al., The American Journal of Human Genetics - This episode covers Nicastro et al. (2025), who identify bi-allelic POPDC2 variants in four families causing a recessive cardiac syndrome marked by sinus-node dysfunction, atrioventricular conduction defects and, in some cases, hypertrophic cardiomyopathy. The study combines genetic sequencing, structural modeling, electrophysiology, tissue analyses and population biobank data to link impaired cAMP binding and loss of POPDC2 modulation of TREK-1 to the phenotype and to show heterozygous carriers are unlikely to be clinically affected. Key terms: POPDC2, cardiac conduction defects, hypertrophic cardiomyopathy, TREK-1, cAMP binding.

Study Highlights:
Researchers found homozygous or compound heterozygous POPDC2 variants in multiple families with early-onset sinus-node disease, AV block and occasional HCM. Homology models and AlphaMissense predict the variants impair cAMP binding and dimerization of POPDC2. In vitro, mutant POPDC2 failed to increase TREK-1 current density and muscle biopsy showed reduced POPDC1/POPDC2 abundance. Population analysis across >1 million individuals found no disease association for heterozygous carriers, supporting a recessive mode of inheritance.

Conclusion:
Bi-allelic loss-of-function POPDC2 variants cause a Mendelian autosomal recessive cardiac syndrome involving conduction disease and sometimes HCM; functional data implicate impaired cAMP binding and reduced TREK-1 regulation, and heterozygous carriers are unlikely to develop clinical disease based on population analyses.

Music:
Enjoy the music based on this article at the end of the episode.

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

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-06.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited the scientific content segments: genetic etiology (POPDC2 LOF and autosomal recessive syndrome), structural modeling and cAMP binding, in vitro TREK-1 electrophysiology, simulation data linking TREK-1 changes to pacemaking, single-cell/transcriptomic localization in AV/sinus nodes, population-biob
- transcript topics: POPDC2 bi-allelic LOF variants and autosomal recessive cardiac syndrome; Structural modeling and predicted disruption of cAMP binding; TREK-1 electrophysiology and POPDC2 interaction in cells; In silico cardiac simulations linking TREK-1 reduction to bradycardia; Population genetics: heterozygous carrier analyses in biobanks; Single-cell and spatial transcriptomics of POPDC1/POPDC2 in AV node and sinus node

QC Summary:
- factual s...