Effect of clinical phenotype on yield of long QT syndrome genetic testing.

Objectives: The purpose of this study was to examine the effect of clinical phenotype on the yield of genetic testing for congenital long QT syndrome (LQTS).

Background: Since the discovery of the first LQTS susceptibility genes in 1995, numerous genotype-phenotype relationships have emerged during the past decade of research genetic testing. In May 2004, LQTS genetic testing became a clinically available molecular diagnostic test.

Methods: Blinded to genetic test results, analysis of the clinical phenotype was performed in 541 consecutive unrelated patients referred to Mayo Clinic's Sudden Death Genomics Laboratory for LQTS genetic testing from August 1997 to July 2004.

Results: The yield of genetic testing correlated significantly with the corrected QT interval (QTc) and clinical diagnostic score ranging from 0% when QTc was <400 ms to 62% when QTc was >480 ms (p < 0.0001). Among those with the highest clinical probability, the yield was 72% (89 of 123). The yield fluctuated substantially depending on age at diagnosis in males. Among physicians who referred > or =5 patients, the yield ranged from 0% to 80% (p < 0.0001).

Conclusions: In this large cohort of unrelated patients referred for LQTS genetic testing, the clinical phenotype strongly correlated with the likelihood of elucidating a pathogenic mutation with the cardiac channel gene screen.