Long QT syndrome caused by a large duplication in the KCNH2 (HERG) gene undetectable by current polymerase chain reaction-based exon-scanning methodologies

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.