Description:
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<jats:title>Background—</jats:title>
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Homozygous or compound heterozygous mutations in
<jats:italic>KCNQ1</jats:italic>
cause Jervell and Lange-Nielsen syndrome, a rare, autosomal-recessive form of long-QT syndrome characterized by deafness, marked QT prolongation, and a high risk of sudden death. However, it is not understood why some individuals with mutations on both
<jats:italic>KCNQ1</jats:italic>
alleles present without deafness. In this study, we sought to determine the prevalence and genetic determinants of this phenomenon in a large referral population of patients with long-QT syndrome.
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<jats:title>Methods and Results—</jats:title>
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A retrospective analysis of all patients with long-QT syndrome evaluated from July 1998 to April 2012 was used to identify those with ≥1
<jats:italic>KCNQ1</jats:italic>
mutation. Of the 249
<jats:italic>KCNQ1</jats:italic>
-positive patients identified, 15 (6.0%) harbored a rare putative pathogenic mutation on both
<jats:italic>KCNQ1</jats:italic>
alleles. Surprisingly, 11 of these patients (73%) presented without the sensorineural deafness associated with Jervell and Lange-Nielsen syndrome. The degree of QT-interval prolongation and the number of breakthrough cardiac events were similar between patients with and without deafness. Interestingly, truncating mutations were more prevalent in patients with Jervell and Lange-Nielsen syndrome (79%) than in nondeaf patients (36%;
<jats:italic>P</jats:italic>
<0.001) derived from this study and those in the literature.
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<jats:title>Conclusions—</jats:title>
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In this study, we provide evidence that the recessive inheritance of a severe long-QT syndrome type 1 phenotype in the absence of an auditory phenotype may represent a more common pattern of long-QT syndrome inheritance than previously anticipated and that these cases should be treated as a higher-risk long-QT syndrome subset similar to their Jervell and Lange-Nielsen syndrome counterparts. Furthermore, mutation type may serve as a genetic determinant of deafness, but not cardiac expressivity, in individuals harboring ≥1
<jats:italic>KCNQ1</jats:italic>
mutation on each allele.
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