Background:
Long QT Syndrome (LQTS) genetic testing has been available clinically since August 2004. In cases of bona fide LQTS, the yield of genetic testing is approximately 75%. Recently (HRS 2007), Priori and colleagues have suggested that referral for LQTS genetic testing should be based on the screening QTc citing a yield of < 2% for cases referred to their research program with a QTc < 440 ms. Here, we analyze the effect of QTc on the yield in two of the largest assembled cohorts of unrelated patients (pts) referred for LQTS genetic testing.
Methods:
From August 1997 to July 2006, 1125 unrelated pts (717 females, average age at diagnosis 23.5 yrs, average QTc 473 ms) were referred to either the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory (N = 541) for research-based LQTS genetic testing or to PGxHealth (N = 574) for the
FAMILION
®
LQTS genetic test. Comprehensive open reading frame and splice site analysis (60 exons) for LQTS-causing mutations involving
KCNQ1
(LQT1),
KCNH2
(LQT2),
SCN5A
(LQT3),
KCNE1
(LQT5), and
KCNE2
(LQT6) was conducted by either dHPLC/DNA sequencing (Mayo), or by direct DNA sequencing (FAMILION).
Results:
The probability of a positive genetic test increased dramatically with increasing QTc, ranging from 5% for the 38 pts referred for genetic testing despite a QTc < 400 ms to 60% for the 168 pts with a QTc > 500 ms (p < 0.00001). Akin to the Priori cohort, the yield of the genetic test was similar among the subset of pts with a QTc < 470 ms (64% Priori, 61% Mayo cohort, and 53% FAMILION, p = NS). However, the yield for those pts with a QTc between 440 and 470 ms was much greater in the Mayo (49%) and FAMILION (36%) cohorts compared to the Priori cohort (14%, p < 0.0005). In contrast to the 2% yield observed in Italy, 22% of pts with QTc < 440 ms referred to Mayo Clinic and 14.5% of the FAMILION referrals had a positive genetic test (p < 0.001).
Conclusions:
Whereas only 2% of patients with a QTc < 440 ms had a positive genetic test in Italy, the yield was ten times greater among those referred to Mayo Clinic despite the same QTc cut-off. The cumulative index of suspicion for LQTS rather than a pre-specified QTc cut-off should guide clinical decision making as to the appropriate utilization of the genetic test.
Access, uptake and communication of genetic test results in Australian families with long QT syndrome (LQTS)