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Keywords {🔍}

pubmed, article, pots, google, scholar, genes, variants, cas, gene, analysis, genetic, function, study, patients, muscle, central, heart, association, autonomic, significance, dysfunction, table, rare, tachycardia, cell, syndrome, subjects, cohort, family, including, related, blood, gwas, system, genomewide, identified, common, postural, orthostatic, human, muscular, plp, role, burden, vascular, cells, european, control, sets, rate,

Topics {✒️}

mcas + wolff-parkinson-white syndrome + leigh disease genome-wide association studies dab2ip-ask1-jnk signaling pathway achieving genome-wide significance genome-wide association analyses genome-wide snp markers ras gtpase-activating protein emery–dreifuss muscular dystrophy gene-based association test flexible gene-based testing postural tachycardia syndrome trans-ethnic association study gene-wide burden test binding cytoplasmic f-actin renin-angiotensin system activity article download pdf case–control association test high-throughput sequencing data ventricular cardiomyopathy-overlap syndromes human genetics population-based linkage analyses establish nuclear-cytoskeletal connections gene-based gwas study auto-chromosomal genotyping data extended thoracic hypovolemia—estrogen genome-wide significance cell–cell junctions play gene-set analysis enhances genome-wide significant full access impaired norepinephrine reuptake—estrogen genome-wide genotyping genome-wide imputation heavy chain subunit kelm rj jr privacy choices/manage cookies chronic fatigue syndrome specific heavy chain polg-related disorders typically gender-related autonomic differences genetic association test central control genetic variation small-fiber neuropathy normalized genome coverage gov/clinvar/variation/930161/ calcium channel blockers sinnegger-brauns mj inappropriate sinus tachycardia rare coding variants

Questions {❓}

• Porges SW, Heilman KJ, Bazhenova OV, Bal E, Doussard-Roosevelt JA, Koledin M (2007) Does motor activity during psychophysiological paradigms confound the quantification and interpretation of heart rate and heart rate variability measures in young children?
• Schondorf R, Low PA (1993) Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia?
• Sun Y, Lu X, Danser AHJ (2020) Megalin: a novel determinant of renin-angiotensin system activity in the kidney?

Schema {🗺️}

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         headline:The genetic landscape of pediatric postural orthostatic tachycardia syndrome
         description:Postural orthostatic tachycardia syndrome (POTS) is a complex disorder with serious health consequences, while its etiology remains largely elusive. The purpose of this study was to investigate the genetic landscape of POTS using genomic approaches in a unique pediatric cohort. We conducted a combined genome wide genotyping and whole exome sequencing (WES) study to systemically examine the molecular mechanisms of POTS pathogenesis. The patients were genotyped as two independent cohorts: a family cohort of 100 complete families and a case–control cohort of 207 unrelated European cases and 4063 ethnicity-matched control subjects. The WES component consisted of a subset of the genotyped subjects, including 87 unrelated European cases and 2719 unrelated European control subjects. The heterogeneous phenotype of POTS made achieving genome-wide significance improbable. Instead, 5670 SNPs with nominal significance (P < 0.05) were identified in both the family and case–control cohorts, with effects in the same direction. We conducted an over-representation analysis (ORA) by considering all genes that showed nominal significance. The ORA identified gene sets linked to cell–cell junction, early estrogen response, and substance-related disorders with statistical significance. Moreover, WES revealed 55 genes with genome-wide significance through rare variant burden analysis, harboring 92 variants classified as pathogenic or likely pathogenic by ClinVar. This study showcases the complex interplay between common and rare genetic variants in POTS development, marking a pioneering step forward in deciphering its complex etiologies. The insights from this research enrich our understanding of POTS, offering new avenues for precise treatment strategies and highlighting areas for further research.
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      description:Postural orthostatic tachycardia syndrome (POTS) is a complex disorder with serious health consequences, while its etiology remains largely elusive. The purpose of this study was to investigate the genetic landscape of POTS using genomic approaches in a unique pediatric cohort. We conducted a combined genome wide genotyping and whole exome sequencing (WES) study to systemically examine the molecular mechanisms of POTS pathogenesis. The patients were genotyped as two independent cohorts: a family cohort of 100 complete families and a case–control cohort of 207 unrelated European cases and 4063 ethnicity-matched control subjects. The WES component consisted of a subset of the genotyped subjects, including 87 unrelated European cases and 2719 unrelated European control subjects. The heterogeneous phenotype of POTS made achieving genome-wide significance improbable. Instead, 5670 SNPs with nominal significance (P < 0.05) were identified in both the family and case–control cohorts, with effects in the same direction. We conducted an over-representation analysis (ORA) by considering all genes that showed nominal significance. The ORA identified gene sets linked to cell–cell junction, early estrogen response, and substance-related disorders with statistical significance. Moreover, WES revealed 55 genes with genome-wide significance through rare variant burden analysis, harboring 92 variants classified as pathogenic or likely pathogenic by ClinVar. This study showcases the complex interplay between common and rare genetic variants in POTS development, marking a pioneering step forward in deciphering its complex etiologies. The insights from this research enrich our understanding of POTS, offering new avenues for precise treatment strategies and highlighting areas for further research.
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            name:Children’s Hospital of Philadelphia
            address:
               name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
               type:PostalAddress
            type:Organization
            name:University of Pennsylvania
            address:
               name:Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
               type:PostalAddress
            type:Organization
            name:Children’s Hospital of Philadelphia
            address:
               name:Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, USA
               type:PostalAddress
            type:Organization
            name:Division of Pulmonary Medicine Children’s Hospital of Philadelphia
            address:
               name:Division of Pulmonary Medicine Children’s Hospital of Philadelphia, Philadelphia, USA
               type:PostalAddress
            type:Organization
            name:University of Iceland
            address:
               name:Faculty of Medicine, University of Iceland, Reykjavik, Iceland
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, USA
      name:Jeffrey R. Boris, MD LLC, Moylan, USA
      name:The Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania, USA
      name:Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, USA
      name:Division of Pulmonary Medicine Children’s Hospital of Philadelphia, Philadelphia, USA
      name:Faculty of Medicine, University of Iceland, Reykjavik, Iceland

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