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ABSTRACT

  • Long QT syndrome is characterized clinically by (a) recurrent syncope; (b) sudden death and aborted sudden death; (c) episodic ventricular tachyarrhythmias such as torsade de pointes and ventricular fibrillation; and (d) prolongation of the QT interval on surface electrocardiogram. In some cases, long QT syndrome is associated with simple syndactyly. This disorder is inherited as an autosomal dominant trait (Romano-Ward syndrome; MIM 192500, 152427, 600163, 600919, 601005, and 176261). Long QT syndrome can be associated with congenital deafness in the Jervell and Lange-Nielsen syndrome (MIM 220400). In this disorder, congenital deafness is inherited as an autosomal recessive trait. Prolongation of the QT interval and arrhythmia susceptibility is inherited as an autosomal semidominant trait—that is, homozygotes are more severely affected than heterozygotes.

  • The frequency of heterozygotes for all dominant long QT syndromes is estimated to be 1 in 10,000 persons. Risk of sudden death in heterozygotes is approximately 0.5 percent per year.

  • Homozygotes are rare. They have profound prolongation of the QT interval and risk of arrhythmia. Untreated, most homozygotes die in childhood.

  • Idiopathic ventricular fibrillation (MIM 600163) is characterized clinically by (a) sudden death and aborted sudden death; (b) episodic ventricular fibrillation; and (c) variable electrocardiographic findings including prolongation of the QRS complex with a right bundle branch block pattern (Brugada syndrome). This disorder is inherited as an autosomal dominant trait. Prevalence is not known.

  • The primary defect in long QT syndrome and idiopathic ventricular fibrillation is a mutation in a gene encoding a cardiac myocyte ion channel. Genes identified to date include KVLQT1 (GenBank U89364), KCNE1 or minK (GenBank L33815), and HERG (GenBank U04270), which encode potassium channel subunits, and SCN5A (GenBank M77235), which encodes the cardiac sodium channel. These proteins are located on the surface of cardiac myocytes and regulate configuration of the cardiac action potential.

  • KVLQT1, gene symbol for potassium voltage-gated channel KQT-like subfamily -member 1- is located on the short arm of chromosomal 11. It comprises 16 exons that span 400 kb. The gene encodes a protein of 676 amino acids. More than 78 different mutant alleles have been identified, which represents 45 percent of the arrhythmia-associated mutations discovered.

  • HERG is located on the long arm of chromosome 7. It comprises 16 exons that span 55 kb. The gene encodes a protein of 1159 amino acids. More than 81 mutations of HERG have been identified thus far. This represents 45 percent of the long QT-associated mutations.

  • SCN5A, gene symbol for sodium channel voltage-gated -type V-α-protein, is located on the short arm of chromosome 3. It comprises 28 exons that span 80 kb. The gene encodes a single protein that contains 2016 amino acids. Thirteen distinct SCN5A mutations have been associated with long QT syndrome. Several SCN5A mutations have been associated with idiopathic ventricular fibrillation.

  • KCNE1 encoding minK is located on the short arm of chromosome 21. It comprises 3 exons that span 4 kb. The gene encodes a protein that contains 129 amino acids. Three missense mutations ...

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