Background: The numerous mutations in the long QT syndrome (LQTS)-associated genes reported to date are point mutations or small insertions and deletions in coding regions or at splice junctions.
Objectives: The purpose of this study was to determine the relative copy number of gene exons in a series of mutation-negative LQTS probands.
Methods: We used a quantitative multiplex approach because the polymerase chain reaction (PCR)-based exon-scanning methodologies routinely utilized in mutation analysis are unable to detect large genomic alterations.
Results: We identified the first large gene rearrangement consisting of a tandem duplication of 3.7 kb in KCNH2 responsible for LQTS in a Dutch family. This large duplication is expected to lead to nonfunctional or severely debilitated channels, thereby decreasing I(Kr).
Conclusion: Our findings have implications for genetic testing in the approximately 30% of LQTS patients in whom conventional mutation screening fails to uncover a mutation. Analysis for large gene alterations such as the one described herein in routine genetic testing may provide a genetic diagnosis in a number of these patients.