Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome

John R. Giudicessi, Jamie D. Kapplinger, David J. Tester, Marielle Alders, Benjamin A. Salisbury, Arthur A.M. Wilde, Michael J. Ackerman

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Background: Hundreds of nonsynonymous single nucleotide variants (nsSNVs) have been identified in the 2 most common long-QT syndrome-susceptibility genes (KCNQ1 and KCNH2). Unfortunately, an ≈3% background rate of rare KCNQ1 and KCNH2 nsSNVs amongst healthy individuals complicates the ability to distinguish rare pathogenic mutations from similarly rare yet presumably innocuous variants. Methods and Results: In this study, 4 tools [(1) conservation across species, (2) Grantham values, (3) sorting intolerant from tolerant, and (4) polymorphism phenotyping] were used to predict pathogenic or benign status for nsSNVs identified across 388 clinically definite long-QT syndrome cases and 1344 ostensibly healthy controls. From these data, estimated predictive values were determined for each tool independently, in concert with previously published protein topology-derived estimated predictive values, and synergistically when =3 tools were in agreement. Overall, all 4 tools displayed a statistically significant ability to distinguish between case-derived and control-derived nsSNVs in KCNQ1, whereas each tool, except Grantham values, displayed a similar ability to differentiate KCNH2 nsSNVs. Collectively, when at least 3 of the 4 tools agreed on the pathogenic status of C-terminal nsSNVs located outside the KCNH2/Kv11.1 cyclic nucleotide-binding domain, the topology-specific estimated predictive value improved from 56% to 91%. Conclusions: Although in silico prediction tools should not be used to predict independently the pathogenicity of a novel, rare nSNV, our results support the potential clinical use of the synergistic utility of these tools to enhance the classification of nsSNVs, particularly for Kv11.1's difficult to interpret C-terminal region.

Original languageEnglish (US)
Pages (from-to)519-528
Number of pages10
JournalCirculation: Cardiovascular Genetics
Volume5
Issue number5
DOIs
StatePublished - Oct 1 2012

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Keywords

  • Genetic variation
  • Genetics
  • Ion channels
  • Long-QT syndrome
  • Pediatrics

ASJC Scopus subject areas

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

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