A novel mutation in KVLQT1, L122P, found in a family with autosomal dominant long QT syndrome

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 underwent 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 amplified 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 individuals 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.)