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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 dimeric homology model of POPDC2 predicted all disease variants we identified in the homozygous or compound heterozygous state to critically affect cAMP binding.
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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 variant leads to the substitution of five residues with a single histidine residue (p.Gln172_Tyr176delinsHis; Figure 2B), and another two (p.Trp188Ter/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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Leu37Serfs20; Figure 2C) are expected to produce a truncated protein, all of which are expected to critically affect 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 addition, both transcripts could be subject to nonsense-mediated decay, which would result in no protein product being made.
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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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While the p.Arg263His and p.Arg263Cys variants are not predicted to disrupt protein folding, they are expected to eliminate a key interaction predicted to stabilize cAMP binding.
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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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Based on these predictions, we hypothesize that cAMP binding is critical for POPDC2 function and, when affected, causes disease.
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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 heterozygous POPDC2 variants have been proposed to increase susceptibility for cardiac conduction disease in humans by Rinné et al., no Mendelian recessive disorder has been linked to this gene so far.
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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 study by Rinné et al., a heterozygous nonsense variant in POPDC2 (p.Trp188Ter; rs144241265, allele frequency of 1.70 × 10 among European individuals in gnomAD) was identified in the heterozygous state in a monozygotic twin pair presenting with AV block and in an unrelated family with a mother and son both diagnosed with first-degree AV block (i.e., prolongation of the PR-interval on the ECG).
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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 twin pair inherited the variant from the unaffected mother, indicating that it does not fully explain the phenotype observed in the two 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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In support of this, single-variant analysis that we conducted in 162 carriers of the p.Trp188Ter variant in more than 1 million individuals from the general population did not show an association with sinus node or AV node conduction disease in heterozygous 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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Thus, while the findings from Rinné et al. are interesting and support our findings, they do not establish pathogenic genetic variation in POPDC2 as a (recessive or dominant) Mendelian cause of cardiac conduction 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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Based on our findings, we recommend the inclusion of POPDC2 in clinical genetic-testing panels for affected individuals presenting with unexplained sinus node dysfunction, AV conduction defects with or without 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 population-level genetic data of more than 1 million individuals, we showed that none of the variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up.
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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 POPDC1 and POPDC3 have been associated with muscular dystrophy, with and without CCD, respectively, while the affected individuals reported here presented with isolated cardiac disease.
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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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Specifically, none of the affected individuals reported muscular weakness, atrophy, or cramps.
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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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Furthermore, muscle biopsy in the proband from family A did not show evident signs of muscle disease.
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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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Also, in contrast to POPDC1- and PODPC3-affected individuals, normal serum creatine kinase levels were found in the affected individuals reported here.
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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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While we did not detect a muscular phenotype in the affected individuals, currently aged 22–50 years, we cannot exclude subtle or age-dependent expression of muscular defects in POPDC2-related disease.
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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 all three POPDC proteins are expressed in both skeletal and cardiac muscle, differences in levels of expression between the POPDC proteins might, in part, determine phenotypic expression.
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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, POPDC2 is predominantly expressed in cardiac tissue, whereas POPDC3, which presents with isolated muscular dystrophy, has a predominant expression in skeletal 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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Western blot analysis and immunostaining of POPDC1 and POPDC2 in muscle biopsies obtained in the proband from family A showed significant reduction of the expression of both POPDC1 and 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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These findings are in line with previous studies that suggested that stability and/or membrane trafficking of the POPDC1-POPDC2 complex is impaired by 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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Using spatial transcriptomics and scRNA-seq from human hearts, we showed 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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On the other hand, in the sinus node, POPDC2 was abundantly expressed, 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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While these results support the observed predisposition to AV node disease in affected individuals with POPDC2 LOF variants, proper statistical testing using pseudo-bulk counts was not possible due to a low number of donors with conduction-system data.
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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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Therefore, these results should be treated as hypothesis generating.
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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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POPDC proteins are established interacting partners of the potassium channel TREK-1, which is known to underlie a background potassium current and is highly expressed in 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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Co-expression of TREK-1 with any of the three POPDC proteins leads to an increase in TREK-1 current, a process modulated by the level of 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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Furthermore, cardiac-specific TREK-1-deficient mice display a sinus node phenotype characterized by bradycardia with frequent episodes of sinus pauses, partially resembling the phenotype in the affected individuals with POPDC2 variants presented here.
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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 an effort to shed light on the electrophysiological mechanism by which the variants in POPDC2 lead to bradycardia, we therefore conducted co-expression studies of WT and mutant POPDC2 with TREK-1.
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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 vitro, both POPDC2 variants tested failed to increase TREK-1 current and, by virtue of observations of bradycardia in TREK-1-deficient mice, these variants would be expected to be associated with bradycardia.
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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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Notwithstanding the clear observation of bradycardia in TREK-1-deficient mice, how loss of background potassium current, causing an increase in diastolic net inward current, leads to bradycardia and sinus pauses is unclear.
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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 in silico modeling studies showed that a 41% reduction of TREK-1 current, simulating the effect of the variants in POPDC2, leads to an increase in diastolic depolarization rate and spontaneous firing.
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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 are in agreement with experiments using isolated sinus node cells of TREK-1-deficient mice and computer simulations using a rabbit sinus node cell 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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In a murine cardiac muscle cell line (HL-1), a stop variant in Popdc2 associated with TREK-1 reduction, the maximum diastolic potential (MDP) was depolarized and the action potential upstroke velocity was reduced.
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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 addition, a slower spontaneous firing rate was 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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In contrast, another study that examined loss of TREK-1 channel function in HL-1 cells showed an increase in spontaneous firing 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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Bradycardia may also be induced via changes in excitability of atrial cardiomyocytes 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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In our simulated human atrial cell, reduction in TREK-1 current density slightly depolarized the MDP and increased the APD, consistent with findings in rat ventricular myocytes, but the excitability was hardly affected.
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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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Thus, while collectively these data support a role for TREK-1 in cardiac pacing and a causal effect of POPDC2 variants through modulation of TREK-1 current, the exact cellular electrophysiological mechanism remains unclear.
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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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Differences in the cellular models used cannot be excluded.
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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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Furthermore, the differences in effects of TREK-1 deficiency observed in vivo and in vitro in TREK-1-deficient mice suggest that other factors (such as altered sympathetic or parasympathetic stimulation in vivo) also contribute to the bradycardia observed at baseline in these mice.
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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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While an effect through modulation of sodium channel function could be postulated, no such effect was observed in our patch-clamp studies.
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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 cardiac arrhythmias in affected individuals with recessive POPDC2 variants are consistent with observations in mice and zebrafish, the role of POPDC2 in cardiac hypertrophy remains unexplained.
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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 of the potential mechanisms underlying cardiac hypertrophy in affected individuals with recessive variants in POPDC2 is modulation of TREK-1.
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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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Since TREK-1 is activated by biomechanical stretch, the role of TREK-1 in cardiac responses to chronic pressure was recently studied using transverse aortic constriction.
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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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Notably, while no clear structural cardiac differences were seen at baseline, mice lacking TREK-1 exhibited an exaggerated pressure-overload-induced concentric hypertrophy with preserved systolic and diastolic cardiac function compared to WT mice.
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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 (II-1 in Figure 1A) 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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We therefore cannot exclude a causal role of myocarditis in this case.
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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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However, (1) the conduction phenotype fits with the phenotypic characteristic of the other five affected individuals we report here; (2) the affected individual carried bi-allelic truncating variants in POPDC2 likely to result in complete LOF, which is a known mechanism for disease in animal models; (3) there was no individual among 125,748 exomes and 15,708 genomes in gnomAD that carried both variants found in compound heterozygosity (p.Trp188Ter and p.Leu37Serfs20) in the affected individual from family D; (4) gnomAD contains 70 predicted LOF POPDC2 variants and none of them occurs in the homozygous state; and (5) knockin mice of the p.Trp188Ter variant (found in compound heterozygosity in family D) displayed stress-induced sinus bradycardia and pauses.
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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 aggregate, these data suggest a causal role for these variants 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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While at this stage speculative, some of the genetic cardiomyopathies (in particular in DSP) are associated with intermittent myocardial inflammatory episodes that appear clinically similar to myocarditis or sarcoidosis.
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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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Presentation with (recurrent) myocarditis-like episodes has been reported for arrhythmogenic cardiomyopathy (ACM).
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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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Among 560 probands and family members with ACM, Bariani et al. reported an episode resembling myocarditis (i.e., “hot phase”) in 23 cases (5%), particularly in pediatric affected individuals and carriers of desmoplakin (MIM: 125647) 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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Furthermore, in a population-based cohort of 336 consecutive affected individuals with acute myocarditis, a significant enrichment of pathogenic variants in genes associated with dilated or arrhythmogenic cardiomyopathy was found (8%) in comparison with controls (<1%, p = 0.0097).
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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 question remains whether the myocarditis exposed the underlying POPDC2-related conduction disease or whether myocarditis is part of the POPDC2 phenotypic spectrum.
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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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While we find it unlikely, compound heterozygosity of the truncating POPDC2 variants might have been irrelevant in this case, and the phenotype could be fully the consequence of 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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This study is limited by its relatively small sample size, with four families presenting bi-allelic POPDC2 variants, which might have not allowed us to provide the full clinical spectrum of disease associated with recessive POPDC2 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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Finally, while population-level data suggest no clinical manifestations in heterozygous carriers, longer-term clinical follow-up would be needed to confirm this in diverse populations and the heterozygous family members in POPDC2 families.
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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 here provide robust association of bi-allelic variants in POPDC2 with a Mendelian autosomal recessive cardiac syndrome 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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Future studies will help to illuminate the full clinical spectrum of the disease in individuals with bi-allelic variants as well as the clinical presentation of heterozygous carriers, thus elucidating the underlying mechanism of disease.
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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 genetic data from families A–D supporting the current study have not been deposited in a public repository because of ethical restrictions but are available from the corresponding author on request.
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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 PDB coordinates for the POPDC2 homology models are available in 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 thank the families for their participation and collaboration.
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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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N.L. is supported by the 10.13039/501100003246Dutch Research Council (ZonMW VENI and Off-road), The Auxilium & Caritas Tulips Fellowship, and the De Snoo van 't Hoogerhuijs Award.
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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.R.B., A.V.P., and N.L. acknowledge the support from the 10.13039/100002129Dutch Heart Foundation (CVON 2018-30 PREDICT2 and CVON2014-18 CONCOR-GENES to C.R.B.) and the 10.13039/501100003246Netherlands Organisation for Scientific Research (VICI fellowship, 016.150.610, to C.R.B.).
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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 work was supported in part by the 10.13039/100000002NIH awards R35GM128666 (M.V.A.) and T32GM092714 (F.Z.B.), a Sloan Research Fellowship (M.V.A.), and an American Heart Association Fellowship 23PRE1019634 (L.W.).
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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 study makes use of data generated by the DECIPHER community.
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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 full list of centers that contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk.
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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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Funding for the project was provided by the 10.13039/100010269Wellcome Trust.
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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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Website: https://www.deciphergenomics.org/. This project has been made possible in part by the Chan Zuckerberg Foundation (2019-202666) to M. Noseda and the British Heart Foundation and Deutsches Zentrum fur Herz-Kreislauf-Forschung (BHF/DZHK: SP/19/1/34461) to M.Noseda.
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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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M. Noseda and L. Mach were supported by the Rosetrees Trust Intermediate Project Grant (PGS23/100028) British Heart Foundation Centre of Research Excellence (RE/24/130023) and NIHR Imperial Biomedical Research Centre.
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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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L. Mach was further supported by British Heart Foundation Clinical Research Training Fellowship (FS/CRTF/23/24444), British Society for Heart Failure Research Fellowship, and Alexander Jansons Myocarditis UK.
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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 thank 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 (Universite de Nice Sophia Antipolis, France) for sharing the hTREK-1a plasmid.
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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 thank 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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Mohamed Hosny and Magdi Yacoub (Magdi Yacoub Foundation, Egypt) for reviewing the phenotype of affected individuals recruited at their center.
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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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R.T. is supported by the Canada Research Chairs program and the Philippa and Marvin Carsley Chair in cardiovascular 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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The PNC “Hub Life Science- Diagnostica Avanzata (HLS-DA), PNC-E3-2022-23683266– CUP: C43C22001630001” is funded by the Italian Minister of Health.
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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 support of Italian Ministry of Education and Research (MUR) “Dipartimenti di Eccellenza Program 2023–2027” - Dept of Pathophysiology and Transplantation, University of Milan to D.R. and G.P.C. is gratefully acknowledged.
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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 work was promoted within the European Reference Network (ERN) for Rare Neuromuscular Diseases.
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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 thank Sara Teichmann for sharing data on scRNA-seq in 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 graphical abstract was created in https://BioRender.com.
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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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L. Monserrat is a shareholder in Dilemma Solutions SL.
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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.A.C. is an employee of and may own stock in GeneDx.
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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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H.M.A., V.T., G.S., E.V.I., H.H., D.F.G., A.T.S., and K.S. report employment at deCODE Genetics during the conduct of the 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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C.E. reports grants from Abbott Diagnostics and Novo Nordisk outside the submitted work.
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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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K.U.K. reports research support from Intermountain Foundation during the conduct of the 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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L.N. reports a stock option grant from Culmination Bio.
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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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H.B. reports lecture fees from Amgen, MSD, Sanofi Avensis, Bristol Myers Squibb, and Pfizer; grants from Novo Nordic Foundation; and another from Novo Nordic Foundation (shares) outside the submitted work.
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PMC10669966
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PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma
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Liposarcomas (LPSs) are common soft-tissue sarcoma subtypes.
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PMC10669966
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PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma
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There is an unmet clinical need for targeting LPS-subtype-specific highly expressed genes.
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PMC10669966
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PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma
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We investigated RNA sequence data from a large clinical LPS sample series and an in silico transcriptome database consisting of 201 tissue types.
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PMC10669966
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PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma
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We discovered that the PDE3A gene is highly expressed in the myxoid LPS subtype.
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PMC10669966
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PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma
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In addition, PDE3A served as a drug target for PDE3A modulators in LPS cell lines, warranting further studies toward its usage in clinical therapy.
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PMC10669966
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PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma
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Liposarcomas (LPSs) are a heterogeneous group of malignancies that arise from adipose tissue.
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PMC10669966
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PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma
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Although LPSs are among the most common soft-tissue sarcoma subtypes, precision medicine treatments are not currently available.
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PMC10669966
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PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma
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To discover LPS-subtype-specific therapy targets, we investigated RNA sequenced transcriptomes of 131 clinical LPS tissue samples and compared the data with a transcriptome database that contained 20,218 samples from 95 healthy tissues and 106 cancerous tissue types.
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PMC10669966
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PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma
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The identified genes were referred to the NCATS BioPlanet library with Enrichr to analyze upregulated signaling pathways.
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