Theresa A. Beery, PhD, RN
Macaira Dyment, BS
Kerry Howell MS
D. Woodrow Benson, MD, PhD

Long QT Syndrome (LQTS) is an inherited disorder that reflects prolongation of repolarization in the cardiac action potential. It can lead to a sudden onset of a polymorphic ventricular tachycardia called Torsades de Pointes, which can progress to ventricular fibrillation and death. Mutations in both sodium and potassium channels have been found in patients with the LQTS. Genes that have shown causal relationships with LQTS include SCN5A, KVLQT1(KCNQ1), HERG, KCNE1,and KCNE2. LQTS was first diagnosed in this family when a 15-year-old girl experienced syncope during soccer practice. This family came to our attention due to concern about the risk of a 6 year old whose mother is affected. Blood was drawn from fifteen family members representing 4 generations. Seven demonstrated LQTS on 12 Lead Electrocardiograms. We used polymorphic short tandem repeat markers at the known LQTS loci to genotype the 15 members of this kindred. Genotypes indicated linkage to chromosome 11p15.5 (D11S1318, D11S860, D11S932) where the potassium channel, KVLQT1, is encoded. Polymerase chain reaction was used to amplify the coding region of KVLQT1 from genomic DNA, and products were prepared and sequenced using an ABI PRISM 3700 DNA Analyzer (Applied Biosystems). During survey of the KVLQT1 coding region, a G to A transition (G502A), which altered the coding sense from glycine to arginine (Gly168Arg), was identified in the AS2 transmembrane domain. Allele-specific oligonucleotide (ASO) hybridization was used to determine the segregation of Gly168Arg mutation in the kindred; DNA from all clinically affected but from none of the clinically unaffected family members carried the G to A transition. The candidate locus approach allowed an efficient mechanism to uncover the potassium channel mutation causing LQTS in this family.