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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Functional effects of the POPDC2 variants from in silico modeling (A) Fits to the experimental data on TREK-1 currents in absence or presence of wild-type (WT) and mutant POPDC2.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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The fit to the mutant data were obtained by scaling the fit to the WT data by a factor of 0.59. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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B) Membrane potential (top) and associated TREK-1 current (bottom) of a single human sinus nodal pacemaker cell as simulated using the comprehensive mathematical model developed by Fabbri et al. ITREK-1 was introduced into the original model cell using the fits of (A).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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ITREK-1 magnitude was set to 0.12 pA/pF at a membrane potential of +30 mV (C) Cycle length of the simulated single human sinus nodal pacemaker cell as a function of ITREK-1 magnitude. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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D) Membrane potential (top) and associated TREK-1 current (bottom) of a single human atrial cell as simulated using the comprehensive mathematical model developed by Maleckar et al. ITREK-1 was introduced into the original model cell using the fits of (A).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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ITREK-1 magnitude was set to 4.0 pA/pF at a membrane potential of +30 mV. Action potentials were elicited at a rate of 1 Hz with a 1-ms, 20% suprathreshold stimulus current. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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E) Diastolic potential of the simulated single human atrial cell as a function of ITREK-1 magnitude. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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F) Threshold stimulus current of the simulated single human atrial cell as a function of ITREK-1 magnitude.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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One may argue that the POPDC2 variant-induced decrease in ITREK-1 affects pacemaker activity by changing the excitability of the atrial tissue surrounding the sinus node.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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This was assessed in simulations of a human atrial cardiomyocyte after incorporating ITREK-1, which was not represented in the original model cell.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Figure 3D shows the results obtained with an ITREK-1 density of 4.0 pA/pF (at +30 mV).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Simulating the effect of the variants in POPDC2 by lowering the density of ITREK-1 to 59% led to a 0.63-mV depolarization of diastolic potential, a 5.1% decrease in threshold current (Figures 3E and 3F, vertical arrows), and a 23-ms increase in action-potential duration (APD) at 90% repolarization.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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The relatively small effects on diastolic potential and threshold current were obtained with a probably overestimated ITREK-1 density, given the large effect of ITREK-1 on the APD of the original model (Figure 3D, top panel).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Smaller, but qualitatively similar, effects on diastolic potential and threshold current were obtained with lower ITREK-1 densities (Figures 3E and 3F), associated with a less prominent effect of ITREK-1 on the APD of the original model.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Overall, despite the observation of bradycardia in mice lacking TREK-1, findings from our simulation studies do not provide an explanation for the clinically observed sinus bradycardia in individuals with POPDC2 variants based on a decrease in ITREK-1 per se.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Individual II-3 from family A (Figure 1A) underwent muscle biopsy of the m. vastus lateralis (Supplemental information).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Histological analysis disclosed mild fiber size variability and a slight increase of connective tissue.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Neither nuclear centralizations nor fiber splittings were observed.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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No necrotic or degenerated fibers were detected (Figures 4A and 4B).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Non-specific myopathic features and increased connective tissue were previously observed in muscle samples from individuals with pathogenic POPDC1 variants, while affected individuals with POPDC3 variants displayed typical features of muscle dystrophies, although the severity of the histopathological findings differed among affected individuals.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Figure 4Evaluation of muscle biopsy from the proband in family A(A and B) (A) Hematoxylin and eosin (H&E) stain and (B) modified Gomori trichrome (MGT) staining of affected individual and, in the inset, control muscle.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Scale bar, 50 μm.(C) Immunofluorescent staining for caveolin-3 (red), POPDC1 (green), and merge for affected individual.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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The inset shows the corresponding immunofluorescence staining for control.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Scale bar, 50 μm.(D) Immunofluorescent staining for caveolin-3 (red), POPDC2 (green), and merge for affected individual.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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The corresponding control staining is shown in the inset.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Scale bar, 50 μm.(E–G) Ultrastructural findings. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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E) Tubular aggregates in subsarcolemmal region. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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F) Sarcolemma alteration (asterisks). (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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G) Increase in lipid droplets.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Scale bar (E and F), 0.84 μm; (G), 3.33 μm.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Evaluation of muscle biopsy from the proband in family A (A and B) (A) Hematoxylin and eosin (H&E) stain and (B) modified Gomori trichrome (MGT) staining of affected individual and, in the inset, control muscle.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Scale bar, 50 μm. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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C) Immunofluorescent staining for caveolin-3 (red), POPDC1 (green), and merge for affected individual.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
|
The inset shows the corresponding immunofluorescence staining for control.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Scale bar, 50 μm. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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D) Immunofluorescent staining for caveolin-3 (red), POPDC2 (green), and merge for affected individual.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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The corresponding control staining is shown in the inset.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Scale bar, 50 μm. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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E–G) Ultrastructural findings. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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E) Tubular aggregates in subsarcolemmal region. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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F) Sarcolemma alteration (asterisks). (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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G) Increase in lipid droplets.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Scale bar (E and F), 0.84 μm; (G), 3.33 μm.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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In healthy skeletal muscle fibers, POPDC1 and POPDC2 were robustly localized in the sarcolemma.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Conversely, in the affected individuals’ muscle, immunofluorescence staining showed a significant reduction of POPDC1 (Figure 4C) and POPDC2 (Figure 4D) levels.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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On the other hand, the immunofluorescent signal for caveolin-3, which also stains muscle membranes, showed normal distribution and intensity in the muscle sample of the affected individual II-3 from family A (Figure 1A) compared to control.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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The severe reduction of POPDC1 and POPDC2 levels was also documented by SDS-PAGE analysis of muscle protein lysates (Figure S5).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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These findings suggest that POPDC2 p.Gln172_Tyr176delinsHis affects the stability of POPDC2, hampering its membrane localization and leading to the secondary reduction of POPDC1.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Indeed, the stability and/or membrane trafficking of the POPDC1-POPDC2 complex have been found to be impaired by genetic variants in each of the two proteins.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Ultrastructural examination detected the presence of tubular aggregates in few muscle fibers (Figure 4E).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Alterations in the structure of the sarcolemma, characterized by small microvilli-like projections, together with subsarcolemmal vacuoles were also observed.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Basal lamina appeared unstructured and enlarged in some fibers (Figure 4F, asterisks).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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We also noted increased level of lipids, which in some cases were arranged to form rows of droplets (Figure 4G).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Heterogeneous transmission electron microscopy findings were previously observed in muscle samples from affected individuals harboring variants in POPDC1 but not in those with POPDC3 pathogenic variants (MIM: 605824).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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To explore the anatomical distribution of POPDC1-3 expression (POPDC1’s previous official gene name is BVES), we analyzed a previously published Visium Spatial and single-nucleus transcriptomic dataset.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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For the Visium Spatial dataset, annotation of histological tissue sections of the AV node and the sinus node was used and expression of POPDC1-3 was explored across those structures (Figure 5A).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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POPDC2 showed higher expression than POPDC1/BVES and POPDC3.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Cardiomyocyte-rich structures showed higher POPDC2 expression compared to cardiomyocyte-poor regions (e.g., cardiac skeleton or fat) (Figure 5B).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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We then interrogated the co-expression pattern of POPDC1/BVES and POPDC2, as (1) Swan et al. described the necessity of POPDC1-2 co-expression for their trafficking to the cell membrane, which is required for their proper function; and (2) variants in POPDC1/BVES-POPDC2 have also been found to affect the stability and/or membrane trafficking of the complex as corroborated here in the muscle biopsy of the affected individual II-3 from family A (Figure 4).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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The most prominent area where POPDC1/BVES and -2 expression was seen co-localizing in the same Visium spots was the AV node (Figure 5C).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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The sinus node expressed POPDC2, but expression of POPDC1 was sparse (Figure 5B).Figure 5Expression of POPDC1-3 in human hearts(A) Overview of single-nucleus and spatial-transcriptomics data analysis from a previously published human heart cell atlas..(B) Spatial-transcriptomics (Visium) analysis of POPDC1 (BVES), POPDC2, and POPDC3 expression across different anatomical regions and histological microstructures in adult human hearts.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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The anatomical sites sampled included AVN, SAN, left ventricle free wall, left ventricular apex, interventricular septum, left atrium, and right atrium.(C) Percentage of spatial spots where co-expression of both POPDC1/BVES and -2 was detected is shown for each histological feature.(D) POPDC family gene expression across cell types in adult human heart profiled by snRNA-seq (10× Genomics).(E) POPDC1/BVES, -2, and -3 gene expression in cardiomyocyte cell states in adult human hearts.(F) Percentage of cells that co-express POPDC1/BVES and POPDC2 in the same single cardiomyocyte.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Figure created with BioRender.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Error bars indicate the 95% confidence interval.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Expression of POPDC1-3 in human hearts (A) Overview of single-nucleus and spatial-transcriptomics data analysis from a previously published human heart cell atlas.. (B) Spatial-transcriptomics (Visium) analysis of POPDC1 (BVES), POPDC2, and POPDC3 expression across different anatomical regions and histological microstructures in adult human hearts.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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The anatomical sites sampled included AVN, SAN, left ventricle free wall, left ventricular apex, interventricular septum, left atrium, and right atrium. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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C) Percentage of spatial spots where co-expression of both POPDC1/BVES and -2 was detected is shown for each histological feature. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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D) POPDC family gene expression across cell types in adult human heart profiled by snRNA-seq (10× Genomics). (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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E) POPDC1/BVES, -2, and -3 gene expression in cardiomyocyte cell states in adult human hearts. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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F) Percentage of cells that co-express POPDC1/BVES and POPDC2 in the same single cardiomyocyte.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Figure created with BioRender.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Error bars indicate the 95% confidence interval.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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To validate these findings and to explore POPDC1 and -2 co-expression within the same cell, we analyzed snRNA-seq data from eight regions of adult human hearts, including the conduction system.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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POPDC2 expression was almost entirely restricted to atrial and ventricular cardiomyocytes compared to other cell types (Figure 5D).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Other genes from the POPDC family (i.e., POPDC1 and POPDC3) also showed a preferential expression in cardiomyocytes, but their expression was less prevalent than POPDC2.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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The snRNA-seq object was then sub-set to cardiomyocytes only and expression of POPDC1-3 interrogated.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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POPDC2 was expressed in all cardiomyocyte cell states, while POPDC1 showed the highest expression in the pacemaker cells (P cells) of the AV node and the AV bundle cells (Figure 5E).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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The co-expression of POPDC1 and -2 within the same single-cell was most prevalent in AV node P cells and AV bundle cells, which concurs with the spatial transcriptomic data (Figure 5F).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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We then also assessed the cardiac expression of Popdc2 in mice utilizing previously published scRNA-seq data of the sinus node and AV node/His region, dissected from embryonic-day-16.5 mouse hearts.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Consistent with the phenotype observed in the affected individual, Popdc2 was expressed in cardiomyocytes as well as sinus node and AV node/His-region cells (Figure S6), corroborating observations from previous studies in mice and our observations reported here in human hearts (Figures 5A–5F).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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We investigated whether heterozygous carriers of the POPDC2 variants found in families A–D (i.e., p.Gln172_Tyr176delinsHis, p.Arg263His, p.Arg263Cys, p.Trp188Ter, and p.Leu37Serfs20) showed (sub-)clinical manifestations of the recessive POPDC2 syndrome in four large population biobanks (total n = 1,089,031) with genetic data, namely deCODE genetics in Iceland (n = 173,025), UK Biobank (n = 428,503), Copenhagen Hospital Biobank and the Danish Blood Donor study in Denmark (n = 487,356), and Intermountain in Utah, USA (n = 138,006).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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We searched their association with (1) AV block, (2) bradycardia, (3) cardiac arrest, (4) HCM, (5) myocarditis, (6) pacemaker implantation, (7) sinus node dysfunction, and (8) heart rate.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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We detected 426 heterozygous carriers of the five familial POPDC2 variants (p.Gln172_Tyr176delinsHis, n = 62; p.Arg263His, n = 34; p.Arg263Cys, n = 156; p.Trp188Ter, n = 162; and p.Leu37Serfs20, n = 12) among 1,089,031 participants in the included biobanks but no homozygotes or compound heterozygotes.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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None of the variants showed statistical association with (sub-)clinical outcomes after Bonferroni correction, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up (Table S6).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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We then conducted genetic burden analyses, wherein rare variants in POPDC2 are aggregated, with the phenotypes above and muscular dystrophy as this is a clinical hallmark of recessive syndromes associated with the two other members of the POPDC family (i.e., POPDC1 and POPDC3).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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We found a significant association with bradycardia after Bonferroni adjustment (p < 1.4 × 10) for the following variant sets: LOFCADD (p = 3.3 × 10, odds ratio [OR] 1.6, LOF and missense when predicted deleterious with CADD phred score ≥25) and LOF1MISID (p = 2 × 10, OR 1.59, LOF and missense when predicted deleterious by at least one of the following prediction methods: MetaSVM, MetaLR, or CADD phred score ≥25; Table S7).
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Although no association with a clinically relevant phenotype was detected, an association with slow heart rate was seen in heterozygous carriers in the general population.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Whether this has clinical relevance remains to be explored.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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We identified bi-allelic variants in POPDC2 in four families that presented with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects, and HCM.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Using homology modeling, we show that the identified POPDC2 variants are predicted to diminish the ability of POPDC2 to bind cAMP.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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In in vitro electrophysiological studies, we demonstrated that, while co-expression of WT POPDC2 with TREK-1 increased TREK-1 current density, POPDC2 harboring variants found in the affected individuals failed to increase TREK-1 current density.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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scRNA-seq from human hearts demonstrated that co-expression of POPDC1 and -2 was most prevalent in AV node, AV node pacemaker, and AV bundle cells.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Sinus node cells expressed POPDC2 abundantly, but expression of POPDC1 was sparse.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Together, these results concur with predisposition to AV node disease in humans with LOF variants in POPDC1 and POPDC2 and presence of sinus node disease in POPDC2 but not in POPDC1-related disease in human.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Our findings provide evidence for bi-allelic variants in POPDC2 as the cause of a Mendelian autosomal recessive cardiac syndrome.
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Several observations support the causality of the identified POPDC2 variants (encoding p.Gln172_Tyr176delinsHis, p.Arg263His, p.Arg263Cys, p.Trp188Ter, and p.Leu37Serfs20). (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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1) The cardiac arrhythmia phenotype of the affected individuals harboring these variants in the homozygous or compound heterozygous state is similar to observations of sinus pauses and bradycardia that were made in mice lacking Popdc2 and to AV block observed in zebrafish after morpholino knockdown of popdc2. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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2) The variants affect highly conserved residues and are predicted damaging by multiple in silico prediction tools. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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3) The variants are extremely rare in gnomAD and were not found in homozygous state. (
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PMC12256823
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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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4) A change affecting the paralogous residue of Arg263 (families B and C) in POPDC3, p.Arg261Gln, has been associated with muscular dystrophy (MIM: 605824).
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