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.


OBJECTIVE
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).


CONCLUSIONS
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.
Koopmann
Tamara T
TT
Experimental and Molecular Cardiology Group, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Alders
Marielle
M
Jongbloed
Roselie J
RJ
Guerrero
Silvia
S
Mannens
Marcel M A M
MM
Wilde
Arthur A M
AA
Bezzina
Connie R
CR
D000293:Adolescent; D000328:Adult; D004252:DNA Mutational Analysis; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005091:Exons; D005260:Female; D020440:Gene Duplication; D015321:Gene Rearrangement; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008133:Long QT Syndrome / Q000235:genetics*; D009426:Netherlands; D021141:Nucleic Acid Amplification Techniques / Q000379:methods
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human