The ECGs of the boy’s father and maternal grandparents were normal. There was no family history of syncope or sudden death. The resting and exercise ECGs of the 4 affected patients were compared with the 3 unaffected family members. The resting QTc was 586 ± 48 ms in the affected individu- als (range 531 to 647 ms) compared with 446 ± 12 ms in the unaffected group (range 433 to 456 ms, P = .005). Comparing supine and standing ECGs in the affected and unaffected groups, the QTc prolonged by 48 ± 29 ms (range 22 to 89 ms) versus 10 ± 9 ms (range 2 to 20 ms, P = .09). There was no difference in the degree of QTc shortening at peak exercise between the affected and unaffected family members (22 ms vs 15 ms, P = .82). RT interval hysteresis, a recently described marker of LQTS, measured 1 minute into recovery was 30 ± 8 ms in the affected group compared with 6.7 ± 5.7 ms in the unaf- fected group (P = .009). 6 In the patient’s mother, the QTc was unaffected by intravenous lidocaine and shortened by 25 ms after oral and intravenous potassium com- bined with spironolactone. The T-wave configuration on the resting ECG resembled that seen in LQT1, as described by Moss et al. 7 Genomic DNA samples of the proband and 6 family members were isolated from whole blood (Puregene, Gentra Systems, Minneapolis, Minn). The coding regions of 5 putative transmembrane segments (S2-S6) and a putative pore region of the KVLQT1 gene for the The congenital long QT syndrome (LQTS) is an inher- ited cardiac disorder characterized by familial syncope and sudden death in otherwise healthy individuals. The electrocardiographic features of LQTS include QT pro- longation and torsades de pointes. 1 Linkage and muta- tion analysis in LQTS kindreds has demonstrated locus heterogeneity, with causative mutations reported in at least 5 different genes. 2-5 A 12-year-old boy was referred for evaluation of recur- rent syncope associated with a prolonged QT interval on the resting electrocardiogram (Figure 1). Syncope occurred on 9 occasions over a 4-year period immedi- ately after vigorous exercise. Multiple previous investi- gations, including neurologic assessment, electroen- cephalography, echocardiography, and Holter monitoring, all gave normal results. Screening of all immediate family members demonstrated similar ECG changes in both of the patient’s siblings and his mother. From the Division of Cardiology and the Blackburn Cardiovascular Genetics Labo- ratory, Robarts Research Institute, University of Western Ontario. Supported by grants from the Heart and Stroke Foundation of Ontario (NA3397 Krahn and NA3628 Hegele). Submitted June 21, 1999; accepted February 6, 2000. Reprint requests: Andrew Krahn, MD, London Health Sciences Center, University Campus, 339 Windermere Rd, London, Ontario, Canada, N6A 5A5. E-mail: akrahn@julian.uwo.ca Copyright © 2000 by Mosby, Inc. 0002-8703/2000/$12.00 + 0 4/1/106599 doi:10.1067/mhj.2000.106599 A novel mutation in KVLQT1, L122P, found in a family with autosomal dominant long QT syndrome Andrew D. Krahn, MD, Jian Wang, MD, Bonnie Spindler, RN, Allan C. Skanes, MD, Raymond Yee, MD, George J. Klein, MD, and Robert A. Hegele, MD London, Ontario, Canada Background Linkage and mutation analysis in long QT syndrome kindreds has demonstrated locus heterogeneity, with causative mutations reported in at least 5 different genes, including KVLQT1. Methods and Results A 12-year-old male proband with recurrent syncope and a prolonged QT interval under- went clinical assessment and exercise testing along with 3 affected and 3 unaffected family members. The coding regions of 5 putative transmembrane segments (S2-S6) and a putative pore region of the KVLQT1 gene for the proband were ampli- fied with the polymerase chain reaction. DNA sequencing of the KVLQT1 gene of the proband revealed a T→C transversion at the second position of codon 122, which predicted a substitution of proline for leucine (L122P). By using restriction analysis, the L122P was found to be co-segregated with the electrocardiographic abnormalities in the nuclear family. Although the patient’s mother was heterozygous for L122P, neither maternal grandparent was a carrier, suggesting that the mutation arose spontaneously. In comparison, there was a complete absence of the mutation in 1336 alleles from 668 normal indi- viduals of 6 different ethnic backgrounds. Conclusion The KVLQT1 L122P mutation is a rare novel mutation that probably arose spontaneously in this family, leading to long QT syndrome. (Am Heart J 2000;140:146-9.)