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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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A final homology model of POPDC2 was created by replacing residues 128–213 of the AlphaFold Multimer model with residues 128–213 of the SWISS-cAMP model after superimposing the individual Popeye domains.
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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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AlphaMissense was used to generate the predicted pathogenicity of single-amino-acid substitutions and deleted regions.
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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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AlphaMissense uses language modeling to understand amino-acid distributions based on sequence context, then it incorporates structural information using an AlphaFold-derived system to consider a protein’s three-dimensional form when assessing a variants’ impact.
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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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It also utilizes weak labels from population frequency data to refine predictions without human biases.
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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 these models, we evaluated the consequence of POPDC2 variants found in families A–D and five variants that occurred homozygously in individuals from the Genome Aggregation Database v2.1.1 (gnomAD), which are not expected to cause disease (Table S2) Single-nucleus RNA-sequencing (snRNA-seq) data and Visium Spatial gene expression data were obtained from a previously published study.
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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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Processed data of single-cell RNA-sequencing (scRNA-seq)/snRNA-seq and Visium data are available for browsing gene expression and download from the Heart Cell Atlas (https://www.heartcellatlas.org).
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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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Annotated, log-normalized count matrices for both modalities were downloaded and specifically analyzed for expression of POPDC1, -2, and -3 using Scanpy package for Python run in Jupyter Notebook.
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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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Original histological annotation of tissue sections was used.
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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 cell-state annotation was adapted from the original study.
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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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All atrial cardiomyocytes were pooled in one category, and all ventricular cardiomyocytes were pooled together.
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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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From the conduction system cells, sinoatrial node pacemaker (SAN P) cells and Purkinje cells are shown separately; due to low cell numbers, atrioventricular node pacemaker (AVN P) and bundle cells are shown together.
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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 and AV node/His scRNA-seq data from mice were obtained from a previously published study.
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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 these data, t-distributed stochastic neighbor embedding (t-SNE) maps with a perplexity of 50 were generated on the R2 environment Genomics Analysis and Visualization Platform (http://r2.amc.nl).
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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 cells were subsequently clustered into different populations using the t-SNE DBSCAN tool.
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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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Sentinel gene expression was used to characterize the different clusters (e.g., sinus node cells, expressing higher levels of Tbx3, Isl1, and Hcn4).
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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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Thereafter, Popdc1-3 expression intensities were plotted on the t-SNE maps to identify their expression profiles across the present tissue clusters.
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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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hTREK-1a cloned in pIRES2-EGFP was obtained from Drs.
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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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Delphine Bichet and Florian Lesage (Université Nice Sophia Antipolis, France).
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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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Full-length POPDC2 cDNA sequences (NM_001308333-hg19; wild type [WT], c.516_527del: p.
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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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Gln172_Tyr176delinsHis and c.788G>A:p.
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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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Arg263His) were synthesized, cloned into pBluescript IISK+ (GeneCust, Boynes, France), and subsequently subcloned into pIRES-GFP (pCGI).
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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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Details on cell preparation and expression can be found in the 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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INa and TREK-1 currents were measured with ruptured and amphotericin-perforated patch-clamp technique, respectively, using an Axopatch 200B amplifier (Molecular Devices Corporation, Sunnyvale, CA, USA).
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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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Voltage control, data acquisition, and analysis were accomplished using custom software.
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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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INa recordings were low-pass filtered with a cutoff frequency of 5 kHz and digitized at 20 kHz, while this was 2 and 4 kHz, respectively, for TREK-1 current measurements.
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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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Series resistance was compensated by ≥80%, and potentials were corrected for the calculated liquid junction potential.
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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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Cell membrane capacitance (Cm) was calculated by dividing the time constant of the decay of the capacitive transient after a −5-mV voltage step from −40 mV by the series resistance.
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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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Patch pipettes were pulled from borosilicate glass (Harvard Apparatus, UK) and had resistances of 2.5–3.5 MΩ after filling with the solutions as indicated below.
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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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Measurements from a minimum of nine cells from three independent transfections were acquired for each condition.
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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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TREK-1 currents were recorded at 36 ± 0.2°C.
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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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Cells were superfused with solution containing (in mM) NaCl 140, KCl 5.4, CaCl2 1.8, MgCl2 1, glucose 5.5, and HEPES 5 at pH 7.4 (NaOH).
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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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Pipette solution contained (in mM) K-gluc 125, KCl 20, NaCl 5, amphotericin-B 0.88, and HEPES 10 at pH 7.2 (KOH).
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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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TREK-1 currents were measured using 500-ms voltage-clamp steps to test potentials ranging from −100 to +50 mV from a holding potential of −80 mV. The TREK-1 current was measured at the end of the voltage-clamp step and current densities were calculated by dividing current amplitude by Cm.
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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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INa was measured at room temperature using a bath solution containing (in mM) NaCl 20, CsCl 120, CaCl2 1.8, MgCl2 1.0, glucose 5.5, and HEPES 5.0 at pH 7.4 (CsOH).
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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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Pipettes were filled with solution containing (in mM) NaF 10, CsCl 10, CsF 110, EGTA 11, CaCl2 1.0, MgCl2 1.0, Na2ATP 2.0, and 10 HEPES at pH 7.2 (CsOH).
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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 INa density and voltage dependence of activation were determined by 50-ms depolarizing pulses to test potentials ranging from −80 to +40 mV from a holding potential of −120 mV. Voltage-dependent inactivation was obtained by measuring the peak currents during a 50-ms test step to −20 mV, which followed a 500-ms prepulse to membrane potentials between −140 and 0 mV to allow inactivation.
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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 holding potential was −120 mV. All voltage-clamp steps were applied with a 5-s cycle length.
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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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Peak INa was defined as the difference between peak and steady-state 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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Current density was calculated by dividing the measured currents by Cm.
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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 determine the activation characteristics of INa, current-voltage curves were corrected for differences in driving force and normalized to maximum peak current (Imax).
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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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Steady-state activation and inactivation curves were fitted using the Boltzmann equation I/Imax = A/ to determine the membrane potential for half-maximal (in)activation (V1/2) and the slope factor k. Data are presented as mean ± standard error of the mean (SEM).
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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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Statistical analysis was carried out with SigmaStat 3.5 software.
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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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Normality and equal variance assumptions were tested with the Kolmogorov-Smirnov and the Levene median test, respectively.
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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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Groups were compared with one-way ANOVA.
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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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p < 0.05 defines statistical significance.
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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 spontaneous electrical activity of a single human sinus nodal pacemaker cell was simulated using the comprehensive mathematical model developed by Fabbri et al. For simulations of a single human atrial cell, we used the model by Maleckar et al. The CellML code of both models, as available from the CellML Model Repository at https://www.cellml.org/, was edited and run in version 0.9.31.1409 of the Windows based Cellular Open Resource (COR) environment.
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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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TREK-1 currents are not included in both original models.
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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 study whether the homozygous loss LOF variants in POPDC2 contribute to bradycardia via TREK-1 current changes, we fitted our experimental data of the TREK-1 current-voltage relationship (Figure 3A) and implemented the thus-obtained TREK-1 current in both models as a control over a range of TREK-1 current densities.
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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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Subsequently, the TREK-1 density was reduced to 59% of the TREK-1 + POPDC2-WT current according to the effects induced by the POPDC2 variants (Figure 3A) to assess the functional effects of the variants.
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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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All simulations were run for a period of 200 s, which appeared a sufficiently long time to reach steady-state behavior.
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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 analyzed data are from the final 10 s of the 200-s period.
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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 recent availability of population-level cohorts with both clinical as well as whole-genome sequencing and well-imputed array genotyping data now provide the opportunity for orthogonal validation of genetic findings through complementary population-level analysis.
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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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Samples were included from 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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Disease status was obtained from electronic health records and ascertained using the following International Classification of Diseases 10th revision codes: atrioventricular block (I44.1 and I44.2), bradycardia (R00.1), cardiac arrest (I46), hypertrophic cardiomyopathy (I42.1 and I42.2), muscular dystrophy (G71.0), myocarditis (I40, I41 and I51.4), and sinus node dysfunction (I49.5).
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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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Pacemaker implantation was defined based on procedure codes (deCODE: Nomesco Classification of Surgical Procedures [NCSP] codes FPE/FPSE and FPF/FPSF.
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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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Copenhagen Hospital Biobank: NCSP codes FPE/FPSE and FPF/FPSF.
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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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UK Biobank: National Clinical Coding Standards OPCS code K60).
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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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Heart rate was available only in the UK Biobank and deCODE.
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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 the UK Biobank, heart rate was obtained during blood-pressure measurement at assessment.
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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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Both measurements were taken twice, and multiple measurements for one individual were averaged.
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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 deCODE, heart-rate measurements were sourced from electrocardiograms (ECGs) from Landspitali University Hospital in Iceland between 1998 and 2015.
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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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Mean values from sinus-rhythm ECGs were obtained for each individual, which were subsequently standardized and adjusted for age and sex.
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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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Details on each biobank and DNA genotyping and sequencing methods for each biobank can be found in the 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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We defined different models to group together various types of variants:(1)LOF: only LOF variants according to Variant Effect Predictor (VEP).(2)LOFTEE: high-confidence LOF variants according to LOFTEE.(3)LOFCADD: LOF and missense (MIS) when predicted deleterious with CADD phred score ≥ 25.(4)LOF1MISID: LOF and MIS when predicted deleterious by at least one of the following prediction methods: MetaSVM, MetaLR, or CADD phred score ≥ 25.
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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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LOF: only LOF variants according to Variant Effect Predictor (VEP).
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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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LOFTEE: high-confidence LOF variants according to LOFTEE.
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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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LOFCADD: LOF and missense (MIS) when predicted deleterious with CADD phred score ≥ 25.
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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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LOF1MISID: LOF and MIS when predicted deleterious by at least one of the following prediction methods: MetaSVM, MetaLR, or CADD phred score ≥ 25.
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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 all models, we used minor allele frequency (MAF) <2% to select variants for analyses.
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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 case-control analyses, we used logistic regression under an additive model to test for association between carrying an LOF variant in POPDC2 (LOF, MIS according to each model A–D) and phenotypes, in which disease status was the dependent variable and genotype counts as the independent variable.
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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 analyses, we used software developed at deCODE genetics.
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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 testing association with heart rate, measurements were inverse-normal transformed and analyzed using a linear mixed model implemented in BOLT-LMM.
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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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Meta-analysis was performed on the summary results from IS, UK, DK, and US when available, using a fixed-effects inverse-variance-weighted method.
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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 uncover the genetic cause of sinus node disease, AV conduction defects and HCM in a child (age at presentation 11–15 years; family A), we performed whole-exome sequencing in the proband, both parents, and two of his unaffected siblings.
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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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His parents are first cousins (Figure 1, individual II-3 in the pedigree; Tables 1 and S3; Figure S1).Figure 1Bi-allelic variants in POPDC2 cause a recessive syndrome with sinus node disease and atrioventricular conduction defects with HCM(A) Pedigrees of families A–D. Closed symbols indicate 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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Males are indicated by squares and females by circles.
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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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A double line indicates a consanguineous relationship.
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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 arrows point to the probands.
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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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Affected individual 6 from family D (highlighted in the pedigree with a filled red box) was diagnosed with bradycardia resulting in an arrest and first-degree AV block during an episode of fulminant myocarditis.(B) Selection of ECG abnormalities: (1) affected individual II-3 from family A (second-degree AV block type Wenckebach and sinus pause [indicated by an arrowhead]; see Figure S1 for longer Holter registration), (2) affected individual II-4 from family B (second-degree AV block type Wenckebach), affected individual II-3 (non-sustained ventricular tachycardia), and affected individual II-1 (2:1 second-degree AV block) from family C. Arrows point to a non-conducted P wave.
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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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Upper right panel: cardiac MRI at the age of 11–15 years showing marked hypertrophy of the interventricular septum (23 mm, Z score: 16.43; height, 160 cm; weight, 49 kg) in the proband of family A.(C) POPDC2 protein domain structure and location of variants found in 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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AV, atrioventricular; CTD, carboxy-terminal domain; ECD, extracellular domain; ND, genotype not determined; regions I/II/II, transmembrane region 1–3; WT, wild type.
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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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Table 1Clinical characteristics of affected individuals with bi-allelic POPDC2 variantsFamily AFamily BFamily CFamily DII-3II-4II-1II:2II:3II-1POPDC2 variantp.
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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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Gln172_Tyr176delinsHisp.
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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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Arg263Hisp.
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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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Arg263Cysp.
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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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Trp188Ter; p.Leu37Serfs20Effect on TREK1 currentLOFLOFnot testednot testedConsanguinityyesyesnonoSexMMMMMMAge at presentation (years)11–1521–2521–2521–2516–2011–15Symptoms at presentationpalpitationspalpitationsnonenonecardiac arrestchest painCardiac arrhythmia and ECG abnormalitiesCardiac arrestnononoarrest following bradycardiaarrest following bradycardiaMinimum heart rate (BPM)333033N/AN/A67Sinus node diseasesinus pauses (3 s)sinus bradycardianoSA-block sinus pauses (5 s)SA blocksinus arrestnoAV conduction disease2 AVB (type 1)PQ time of 200 mssecond AVBfirst and second AVB (type 1 and 2:1)first AVBfirst and second AVB (type 1)first AVBAtrial arrhythmiaatrial fibrillation and flutternoatrial fibrillation and flutternoepisodes of high atrial ratenoVentricular arrhythmiamonomorphic NSVT, PVCsnomonomorphic NSVTnomonomorphic NSVTVTStructural cardiac and extracardiac abnormalitiesHypertrophic cardiomyopathyyesyesnonononoCardiac MRI findings (mm)septal hypertrophy (23 mm)septal hypertrophy (16mm)N/AN/Apossible myocarditissignificant LV fibrosis and inflammationMyocarditisnonononopossible myocarditisclinically (not on cardiac histology)TreatmentPacemaker implantation (age, years)yes (15)noyes (23)yes (21)yes (17)yes (15), temporaryICD implantation (age, years)yes (15)nononoyes (33)noAppropriate ICD shocksnoN/AN/AN/AnoN/AAVB, atrioventricular block, BPM, beats per minute; ICD, implantable cardiac defibrillator; MRI, magnetic resonance imaging; N/A, not available, NSVT, non-sustained ventricular tachycardia; PVC, premature ventricular contractions; SA, sinoatrial; TTE, transthoracic echocardiogram; VT, ventricular tachycardia.
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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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Bi-allelic variants in POPDC2 cause a recessive syndrome with sinus node disease and atrioventricular conduction defects with HCM (A) Pedigrees of families A–D. Closed symbols indicate affected individuals.
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PMC12256823
|
Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Males are indicated by squares and females by circles.
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PMC12256823
|
Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
|
A double line indicates a consanguineous relationship.
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PMC12256823
|
Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
|
The arrows point to the probands.
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PMC12256823
|
Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.
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Affected individual 6 from family D (highlighted in the pedigree with a filled red box) was diagnosed with bradycardia resulting in an arrest and first-degree AV block during an episode of fulminant myocarditis. (
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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) Selection of ECG abnormalities: (1) affected individual II-3 from family A (second-degree AV block type Wenckebach and sinus pause [indicated by an arrowhead]; see Figure S1 for longer Holter registration), (2) affected individual II-4 from family B (second-degree AV block type Wenckebach), affected individual II-3 (non-sustained ventricular tachycardia), and affected individual II-1 (2:1 second-degree AV block) from family C. Arrows point to a non-conducted P wave.
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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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Upper right panel: cardiac MRI at the age of 11–15 years showing marked hypertrophy of the interventricular septum (23 mm, Z score: 16.43; height, 160 cm; weight, 49 kg) in the proband of family A. (C) POPDC2 protein domain structure and location of variants found in 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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AV, atrioventricular; CTD, carboxy-terminal domain; ECD, extracellular domain; ND, genotype not determined; regions I/II/II, transmembrane region 1–3; WT, wild type.
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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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Clinical characteristics of affected individuals with bi-allelic POPDC2 variants AVB, atrioventricular block, BPM, beats per minute; ICD, implantable cardiac defibrillator; MRI, magnetic resonance imaging; N/A, not available, NSVT, non-sustained ventricular tachycardia; PVC, premature ventricular contractions; SA, sinoatrial; TTE, transthoracic echocardiogram; VT, ventricular tachycardia.
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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 likely causal variant was found in genes previously associated with Mendelian cardiomyopathies or arrhythmia syndromes (either recessive or dominant; Table S4).
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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 line with the expected recessive inheritance pattern, we identified a rare segregating homozygous variant, NM_001308333.2:c.516_527del; NP_001295262.1:p.(Gln172_Tyr176delinsHis), in the Popeye domain-containing protein 2 (POPDC2), as the most likely variant consistent with a recessive mode of inheritance and parental consanguinity (see Table S5 for overview of the two segregating coding-region variants identified in the 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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Of note, the only other homozygous segregating variant has been found 15 times in gnomAD and was therefore found unlikely to cause the disease in this 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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No de novo variants were found in the index 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 cardiac arrhythmia phenotype in the affected individual is consistent with studies in mice that showed that loss of Popdc2 resulted in sinus pauses and bradycardia and with findings made in zebrafish where morpholino knockdown of popdc2 resulted in AV block.
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