Repeat long QT syndrome genetic testing of phenotype-positive cases: Prevalence and etiology of detection misses

Morgan M. Medlock, David J. Tester, Melissa L. Will, J. Martijn Bos, Michael J. Ackerman

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Background: Approximately 75% of long QT syndrome (LQTS) has been explained genetically through research-based and, more recently, commercial genetic testing. While novel LQTS-susceptibility genes or mutations in unexplored regions of known genes underlie the genetic mechanism for some of the 25% "genotype-negative" remnant, it is likely that some cases represent false-negative test results owing to mutation detection failures. Objective: To determine the prevalence and etiology of false negatives that occurred with research-based mutational analysis involving denaturing high-performance liquid chromatography (DHPLC) followed by DNA sequencing (DHPLC-SEQ) in our previously published cohort of unrelated patients referred for LQTS genetic testing. Methods: Forty-four LQTS cases (29 men, average age 23 ± 15 years, average corrected QT interval 516 ± 56 ms) deemed genotype negative following DHPLC-SEQ were selected for repeat genetic testing using direct DNA sequencing. Results: LQTS-causing mutations were identified in 7 of 44 (16%) phenotype-positive/previously genotype-negative subjects, including 4 mutations in KCNQ1 (S225L, G568R, R591H, and R594Q), 2 in KCNH2 (H70R and G925R), and 1 in SCN5A (V411M). None of these variants were seen in more than 2600 reference alleles. Analysis of the misses revealed (1) normal DHPLC detection profile in 2, (2) allelic dropout in 2, (3) failure to correctly optimize DHPLC conditions in 1, and (4) failure to detect abnormal DHPLC signal in 2. Conclusions: Repeat genetic testing using direct DNA sequencing may be warranted for LQTS phenotype-positive individuals who were pronounced genotype negative during the decade of research-based mutational analysis that involved intermediate mutation detection methods such as DHPLC.

Original languageEnglish (US)
Pages (from-to)1977-1982
Number of pages6
JournalHeart rhythm
Issue number12
StatePublished - Dec 2012


  • Genetic testing, Mutation
  • Genetics
  • Genotyping
  • Long QT syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


Dive into the research topics of 'Repeat long QT syndrome genetic testing of phenotype-positive cases: Prevalence and etiology of detection misses'. Together they form a unique fingerprint.

Cite this