Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A -Encoded Na<inf>v</inf>1.5 Cardiac Sodium Channel

Jamie D. Kapplinger, John R. Giudicessi, Dan Ye, David J. Tester, Thomas E. Callis, Carmen R. Valdivia, Jonathan C. Makielski, Arthur A. Wilde, Michael John Ackerman

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Background - A 2% to 5% background rate of rare SCN5A nonsynonymous single nucleotide variants (nsSNVs) among healthy individuals confounds clinical genetic testing. Therefore, the purpose of this study was to enhance interpretation of SCN5A nsSNVs for clinical genetic testing using estimated predictive values derived from protein-topology and 7 in silico tools. Methods and Results - Seven in silico tools were used to assign pathogenic/benign status to nsSNVs from 2888 long-QT syndrome cases, 2111 Brugada syndrome cases, and 8975 controls. Estimated predictive values were determined for each tool across the entire SCN5A-encoded Na<inf>v</inf>1.5 channel as well as for specific topographical regions. In addition, the in silico tools were assessed for their ability to correlate with cellular electrophysiology studies. In long-QT syndrome, transmembrane segments S3-S5+S6 and the DIII/DIV linker region were associated with high probability of pathogenicity. For Brugada syndrome, only the transmembrane spanning domains had a high probability of pathogenicity. Although individual tools distinguished case- and control-derived SCN5A nsSNVs, the composite use of multiple tools resulted in the greatest enhancement of interpretation. The use of the composite score allowed for enhanced interpretation for nsSNVs outside of the topological regions that intrinsically had a high probability of pathogenicity, as well as within the transmembrane spanning domains for Brugada syndrome nsSNVs. Conclusions - We have used a large case/control study to identify regions of Na<inf>v</inf>1.5 associated with a high probability of pathogenicity. Although topology alone would leave the variants outside these identified regions in genetic purgatory, the synergistic use of multiple in silico tools may help promote or demote a variant's pathogenic status.

Original languageEnglish (US)
Pages (from-to)582-595
Number of pages14
JournalCirculation: Cardiovascular Genetics
Volume8
Issue number4
DOIs
StatePublished - Aug 25 2015

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Brugada Syndrome
Long QT Syndrome
Sodium Channels
Nucleotides
Computer Simulation
Virulence
Genetic Testing
S 6
Electrophysiology
varespladib methyl
Case-Control Studies

Keywords

  • Brugada syndrome
  • genetic testing
  • long-QT syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

Cite this

Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A -Encoded Na<inf>v</inf>1.5 Cardiac Sodium Channel. / Kapplinger, Jamie D.; Giudicessi, John R.; Ye, Dan; Tester, David J.; Callis, Thomas E.; Valdivia, Carmen R.; Makielski, Jonathan C.; Wilde, Arthur A.; Ackerman, Michael John.

In: Circulation: Cardiovascular Genetics, Vol. 8, No. 4, 25.08.2015, p. 582-595.

Research output: Contribution to journalArticle

Kapplinger, Jamie D. ; Giudicessi, John R. ; Ye, Dan ; Tester, David J. ; Callis, Thomas E. ; Valdivia, Carmen R. ; Makielski, Jonathan C. ; Wilde, Arthur A. ; Ackerman, Michael John. / Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A -Encoded Na<inf>v</inf>1.5 Cardiac Sodium Channel. In: Circulation: Cardiovascular Genetics. 2015 ; Vol. 8, No. 4. pp. 582-595.
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abstract = "Background - A 2{\%} to 5{\%} background rate of rare SCN5A nonsynonymous single nucleotide variants (nsSNVs) among healthy individuals confounds clinical genetic testing. Therefore, the purpose of this study was to enhance interpretation of SCN5A nsSNVs for clinical genetic testing using estimated predictive values derived from protein-topology and 7 in silico tools. Methods and Results - Seven in silico tools were used to assign pathogenic/benign status to nsSNVs from 2888 long-QT syndrome cases, 2111 Brugada syndrome cases, and 8975 controls. Estimated predictive values were determined for each tool across the entire SCN5A-encoded Nav1.5 channel as well as for specific topographical regions. In addition, the in silico tools were assessed for their ability to correlate with cellular electrophysiology studies. In long-QT syndrome, transmembrane segments S3-S5+S6 and the DIII/DIV linker region were associated with high probability of pathogenicity. For Brugada syndrome, only the transmembrane spanning domains had a high probability of pathogenicity. Although individual tools distinguished case- and control-derived SCN5A nsSNVs, the composite use of multiple tools resulted in the greatest enhancement of interpretation. The use of the composite score allowed for enhanced interpretation for nsSNVs outside of the topological regions that intrinsically had a high probability of pathogenicity, as well as within the transmembrane spanning domains for Brugada syndrome nsSNVs. Conclusions - We have used a large case/control study to identify regions of Nav1.5 associated with a high probability of pathogenicity. Although topology alone would leave the variants outside these identified regions in genetic purgatory, the synergistic use of multiple in silico tools may help promote or demote a variant's pathogenic status.",
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AU - Giudicessi, John R.

AU - Ye, Dan

AU - Tester, David J.

AU - Callis, Thomas E.

AU - Valdivia, Carmen R.

AU - Makielski, Jonathan C.

AU - Wilde, Arthur A.

AU - Ackerman, Michael John

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AB - Background - A 2% to 5% background rate of rare SCN5A nonsynonymous single nucleotide variants (nsSNVs) among healthy individuals confounds clinical genetic testing. Therefore, the purpose of this study was to enhance interpretation of SCN5A nsSNVs for clinical genetic testing using estimated predictive values derived from protein-topology and 7 in silico tools. Methods and Results - Seven in silico tools were used to assign pathogenic/benign status to nsSNVs from 2888 long-QT syndrome cases, 2111 Brugada syndrome cases, and 8975 controls. Estimated predictive values were determined for each tool across the entire SCN5A-encoded Nav1.5 channel as well as for specific topographical regions. In addition, the in silico tools were assessed for their ability to correlate with cellular electrophysiology studies. In long-QT syndrome, transmembrane segments S3-S5+S6 and the DIII/DIV linker region were associated with high probability of pathogenicity. For Brugada syndrome, only the transmembrane spanning domains had a high probability of pathogenicity. Although individual tools distinguished case- and control-derived SCN5A nsSNVs, the composite use of multiple tools resulted in the greatest enhancement of interpretation. The use of the composite score allowed for enhanced interpretation for nsSNVs outside of the topological regions that intrinsically had a high probability of pathogenicity, as well as within the transmembrane spanning domains for Brugada syndrome nsSNVs. Conclusions - We have used a large case/control study to identify regions of Nav1.5 associated with a high probability of pathogenicity. Although topology alone would leave the variants outside these identified regions in genetic purgatory, the synergistic use of multiple in silico tools may help promote or demote a variant's pathogenic status.

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