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

Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. doi: 10.1161/CIRCGENETICS.112.963785. Epub 2012 Sep 4.

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: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Case-Control Studies
  • Computational Biology
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / chemistry
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Humans
  • KCNQ1 Potassium Channel / chemistry
  • KCNQ1 Potassium Channel / genetics
  • KCNQ1 Potassium Channel / metabolism
  • Long QT Syndrome / classification
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / pathology
  • Phenotype
  • Phylogeny
  • Polymorphism, Single Nucleotide
  • Protein Structure, Tertiary
  • Romano-Ward Syndrome / classification
  • Romano-Ward Syndrome / genetics*
  • Romano-Ward Syndrome / pathology

Substances

  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • KCNQ1 Potassium Channel

Supplementary concepts

  • Long Qt Syndrome 2