Screening for copy number variation in genes associated with the long QT syndrome: clinical relevance.

The aim of this study was to investigate, in a set of 93 mutation-negative long QT syndrome (LQTS) probands, the frequency of copy number variants (CNVs) in LQTS genes. LQTS is an inherited cardiac arrhythmia characterized by a prolonged heart rate-corrected QT (QTc) interval associated with sudden cardiac death. Recent studies suggested the involvement of duplications or deletions in the occurrence of LQTS. However, their frequency remains unknown in LQTS patients. Point mutations in KCNQ1, KCNH2, and SCN5A genes were excluded by denaturing high-performance liquid chromatography or direct sequencing. We applied Multiplex Ligation-dependent Probe Amplification (MLPA) to detect CNVs in exons of these 3 genes. Abnormal exon copy numbers were confirmed by quantitative multiplex PCR of short fluorescent fragment (QMPSF). Array-based comparative genomic hybridization (array CGH) analysis was performed using Agilent Human Genome 244K Microarrays to further map the genomic rearrangements. We identified 3 different deletions in 3 unrelated families: 1 in KCNQ1 and 2 involving KCNH2. We showed in the largest family that the deletion involving KCNH2 is fully penetrant and segregates with the long QT phenotype in 7 affected members. Our study demonstrates that CNVs in KCNQ1 and KCNH2 explain around 3% of LQTS in patients with no point mutation in these genes. This percentage is likely higher than the frequency of point mutations in ANKB, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, and SNTA1 together. Thus, we propose that CNV screening in KCNQ1 and KCNH2 may be performed routinely in LQTS patients.

Barc J ，Briec F ，Schmitt S ，Kyndt F ，Le Cunff M ，Baron E ，Vieyres C ，Sacher F ，Redon R ，Le Caignec C ，Le Marec H ，Probst V ，Schott JJ ... -  《-》

Identification of large gene deletions and duplications in KCNQ1 and KCNH2 in patients with long QT syndrome.

Eddy CA ，MacCormick JM ，Chung SK ，Crawford JR ，Love DR ，Rees MI ，Skinner JR ，Shelling AN ... -  《-》

Allelic dropout in long QT syndrome genetic testing: a possible mechanism underlying false-negative results.

Tester DJ ，Cronk LB ，Carr JL ，Schulz V ，Salisbury BA ，Judson RS ，Ackerman MJ ... -  《HEART RHYTHM》

Investigation of ion channel gene variants in patients with long QT syndrome.

Ernesto C ，Cruz FE ，Lima FS ，Coutinho JL ，Silva R ，Urményi TP ，Carvalho AC ，Rondinelli E ... -  《-》

Long QT and Brugada syndrome gene mutations in New Zealand.

Chung SK ，MacCormick JM ，McCulley CH ，Crawford J ，Eddy CA ，Mitchell EA ，Shelling AN ，French JK ，Skinner JR ，Rees MI ... -  《HEART RHYTHM》