4 NOVEL KVLQT1 AND 4 NOVEL HERG MUTATIONS IN FAMILIAL LONG-QT SYNDROME

Background Familial long-QT syndrome (LQTS) is characterized by prolon ged ventricular repolarization. Clinical symptoms include recurrent sy ncopal attacks, and sudden death may occur due to ventricular tachyarr hythmias. Three genes responsible for this syndrome (KVLQT1, HERG, and SCN5A) have been identified so far. We investigated mutations of thes e genes in LQTS families. Methods and Results Thirty-two Japanese fami lies with LQTS were brought together for screening for mutations. Geno mic DNA from each proband was examined by the polymerase chain reactio n-single-strand conformation polymorphism technique followed by direct DNA sequencing. In four of the families, comprising 16 patients, muta tions were identified in KVLQT1; five other families (9 patients) segr egated mutant alleles of HERG. All 25 of these patients carried the sp ecific mutations present in their respective families, and none of 80 normal individuals carried these alleles. Mutations were confirmed by endonuclease digestion or hybridization of mutant allele-specific olig onucleotides. No mutation in SCN5A was found in any family. Conclusion s We identified nine different mutations among 32 families with LQTS. Eight of these were novel and account for 25% of all types of mutation s reported to date. Such a variety of mutations makes it difficult to screen high-risk groups using simple methods such as endonuclease dige stion or mutant allele-specific amplification.