Romano-Ward Long QT Syndrome: Identification of the Gene Responsible for Cardiac Arrhythmia in the First Autosomal Dominant LQT Family, the Ward Kindred • 149

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Background: Long QT syndrome (LQT) is an inherited cardiac arrhythmia that causes sudden death in young, previously healthy individuals. In 1964, the first family of autosomal dominant LQT was reported by OC Ward. Since then, four genes for autosomal dominant LQT were mapped to chromosome 11p 15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT4), and 4q25-27 (LQT4). Genes for LQT1, LQT2, and LQT3 have been identified as KVLQT1, HERG, SCN5A, respectively. However, the gene responsible for the first autosomal dominant LQT family is unknown. We hypothesized that a mutation in either KVLQT1, HERG, or SCN5A would be responsible for the cardiac arrhythmia in this family.

Methods and Results: We used single strand conformation polymorphism and DNA sequence analysis to screen for mutations in KVLQT1, HERG, or SCN5A, in affetced members of the first autosomal dominant LQT family reported by OC Ward. We identified a splicing mutation (SP/Ala213/a-c) of KVLQT1 in the pore region of this potassium channel, which cosegregates with all affetced members of the family, but not with normal individuals of the family nor with more than 150 normal control individuals.

Conclusion: We have established that the cardaic arrhythmia and sudden death in the first autosomal dominant LQT family, the Ward kindred, is the result of a mutation in KVLQT1.

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