MOLECULAR-BASIS OF THE LONG-QT SYNDROME-ASSOCIATED WITH DEAFNESS

Jervell and Lange-Nielsen syndrome:is an autosomal recessive form of l ong-QT syndrome. In addition to QT interval prolongation, this disorde r is associated with congenital deafness. Jervell and Lange-Nielsen sy ndrome is rare, but affected individuals are-susceptible to cardiac ar rhythmias with a high incidence of sudden death and short life expecta ncy. A proband with Jervell and Lange-Nielsen syndrome and family memb ers were ascertained and phenotypically characterized. Linkage, mutati onal, and DNA sequence analyses were used to define the genetic basis of this disorder. We found that the proband had long-QT syndrome and s ensory deafness. Some family members also had QTc prolongation with an autosomal dominant pattern of inheritance, but these patients had nor mal hearing. The gene responsible for QTc prolongation in this family was mapped to chromosome 11p15.5 using linkage analyses. The maximum L OD score at D11S1318 was 5.46, indicating odds greater than 100,000:1 favoring linkage. Mutation analyses revealed a single base pair insert ion in KVLQT1, the potassium channel gene responsible for chromosome I i-linked long-QT syndrome. This mutation caused a premature stop codon . All family members with QTc prolongation, except the proband, were h eterozygous for the mutation. The proband with Jervell and Lange-Niels en syndrome resulted from a consanguineous marriage and was homozygous for the KVLQT1 mutation. Homozygous mutation of KVLQT1 causes Jervell and Lange-Nielsen syndrome. Members of Jervell and Lange-Nielsen synd rome families should be examined for long-QT syndrome, even if they ha ve normal hearing.