Electrocardiographic prediction of abnormal genotype in congenital long QTsyndrome: Experience in 101 related family members

Introduction: Previous studies showed that diagnosing congenital long QT sy ndrome (LQTS) is difficult due to variable penetrance and genetic heterogen eity, especially when subjects from multiple families with diverse mutation s are combined. We hypothesized that a combination of clinical and ECG tech niques could identify gene carriers within a single family with congenital LQTS, Methods and Results: One hundred one genotyped members of a family with LQT S, including 26 carriers of a HERG mutation, underwent history and ECG anal ysis. Forty-eight family members also underwent exercise testing with QT an d T wave alternans (TWA) analysis and 24-hour Holter monitoring with QT and heart rate variability analysis. A logistic regression model, which includ ed age, gender, QTc, and QTc by age, provided the best prediction of gene c arrier status, although there was substantial overlap (78%) of QTc among su bjects with and without the mutation. QTc was not helpful as a discriminato r in children less than or equal to 13 years. TWA (observed infrequently) d id not add significantly to the model's ability to predict abnormal genotyp e, Conclusion: Even in this homogeneous LQTS population, the phenotype was so variable that clinical and detailed ECG analyses did not permit an accurate diagnosis of gene carrier status, especially in children. Sustained microv olt TWA was a specific (100%) but insensitive (18%) marker for LQTS. Its ab ility to predict risk of arrhythmia in this population remains to be determ ined. Genetic testing serves an essential role in screening for carriers of LQTS.