Abstract 13141: Prevalence and Genetic Determinants of Sensorineural Deafness in KCNQ1 Compound Heterozygosity
Introduction: Long QT syndrome (LQTS) is an autosomal dominant condition with an estimated prevalence of 1 in 2000. The most common subtype of LQTS (LQT1) is caused by mutations in the KCNQ1-encoded Kv7.1 potassium channel. The very rare autosomal recessive form of LQT1, Jervell and Lange-Nielsen syndrome (JLNS1), is caused by either homozygous or compound heterozygous mutations involving both KCNQ1 alleles and is characterized by deafness, markedly prolonged QT interval, and a high risk of sudden death. However, it is not understood why some KCNQ1 compound heterozygotes present without deafness. Here, we sought to determine the prevalence and potential genetic determinants of this phenomenon in a large referral population of LQT1 patients.
Methods: Retrospective analysis of all LQTS patients evaluated from July 1998 to April 2012 was used to identify those with ≥ 1 KCNQ1 mutation. Patients with > 1 KCNQ1 mutation but on the same allele, a KCNQ1 mutation observed in > 1 individual in the 1000 genomes or NHLBI exome sequencing projects, or additional mutations in other channelopathic genes were excluded from this study.
Results: Of the 249 Mayo evaluated KCNQ1-positive patients, 14 unrelated patients (5.6%) harbored a rare putative pathogenic mutation on both KCNQ1 alleles. Surprisingly, 10 (71%) KCNQ1 compound heterozygotes presented without the sensorineural deafness typically associated with JLNS. The degree of QT interval prolongation and number of breakthrough cardiac events were statistically similar between non-deaf and JLNS compound heterozygotes. Interestingly, non-deaf compound heterozygotes were significantly more likely to harbor non-truncating (e.g. missense or in-frame deletion) mutations (72%), than JLNS compound heterozygotes (25%, p = 0.03).
Conclusions: Here, we provide evidence that the “recessive” inheritance of a severe LQT1 phenotype in the absence of an auditory phenotype may represent a more common pattern of LQTS inheritance than previously anticipated. Furthermore, mutation type may serve as a genetic determinant of deafness, but not cardiac expressivity, in KCNQ1 compound heterozygosity. Lastly, recessive LQT1 patients should be treated as a higher-risk LQTS population similar to their JLNS counterparts.
- © 2012 by American Heart Association, Inc.