Advanced search
Add to list

A complex double deletion in LMNA underlies progressive cardiac conduction disease, atrial arrhythmias, and sudden death

Author
Organization
Abstract
Background: Cardiac conduction disease is a clinically and genetically heterogeneous disorder characterized by defects in electrical impulse generation and conduction and is associated with sudden cardiac death. Methods and Results: We studied a 4-generation family with autosomal dominant progressive cardiac conduction disease, including atrioventricular conduction block and sinus bradycardia, atrial arrhythmias, and sudden death. Genome-wide linkage analysis mapped the disease locus to chromosome 1p22-q21. Multiplex ligation-dependent probe amplification analysis of the LMNA gene, which encodes the nuclear-envelope protein lamin A/C, revealed a novel gene rearrangement involving a 24-bp inversion flanked by a 3.8-kb deletion upstream and a 7.8-kb deletion downstream. The presence of short inverted sequence homologies at the breakpoint junctions suggested a mutational event involving serial replication slippage in trans during DNA replication. Conclusions: We identified for the first time a complex LMNA gene rearrangement involving a double deletion in a 4-generation Dutch family with progressive conduction system disease. Our findings underscore the fact that if conventional polymerase chain reaction-based direct sequencing approaches for LMNA analysis are negative in suggestive pedigrees, mutation detection techniques capable of detecting gross genomic lesions involving deletions and insertions should be considered.
Keywords
gene rearrangement, LMNA conduction disease, complex deletion, MLPA, LAMIN-A/C GENE, SERIAL REPLICATION SLIPPAGE, DILATED CARDIOMYOPATHY, SYSTEM DISEASE, MUTATIONS, CHANNEL, HEART, LAMINOPATHIES, TRANSCRIPTION, METAANALYSIS

Citation

Please use this url to cite or link to this publication:

MLA
Marsman, Roos F et al. “A Complex Double Deletion in LMNA Underlies Progressive Cardiac Conduction Disease, Atrial Arrhythmias, and Sudden Death.” CIRCULATION-CARDIOVASCULAR GENETICS 4.3 (2011): 280–287. Print.
APA
Marsman, R. F., Bardai, A., Postma, A. V., Res, J. C., Koopmann, T. T., Beekman, L., van der Wal, A. C., et al. (2011). A complex double deletion in LMNA underlies progressive cardiac conduction disease, atrial arrhythmias, and sudden death. CIRCULATION-CARDIOVASCULAR GENETICS, 4(3), 280–287.
Chicago author-date
Marsman, Roos F, Abdenasser Bardai, Alex V Postma, Jan CJ Res, Tamara T Koopmann, Leander Beekman, Allard C van der Wal, et al. 2011. “A Complex Double Deletion in LMNA Underlies Progressive Cardiac Conduction Disease, Atrial Arrhythmias, and Sudden Death.” Circulation-cardiovascular Genetics 4 (3): 280–287.
Chicago author-date (all authors)
Marsman, Roos F, Abdenasser Bardai, Alex V Postma, Jan CJ Res, Tamara T Koopmann, Leander Beekman, Allard C van der Wal, Yigal M Pinto, Ronald H Lekanne Deprez, Arthur AM Wilde, Luc Jordaens, and Connie R Bezzina. 2011. “A Complex Double Deletion in LMNA Underlies Progressive Cardiac Conduction Disease, Atrial Arrhythmias, and Sudden Death.” Circulation-cardiovascular Genetics 4 (3): 280–287.
Vancouver
1.
Marsman RF, Bardai A, Postma AV, Res JC, Koopmann TT, Beekman L, et al. A complex double deletion in LMNA underlies progressive cardiac conduction disease, atrial arrhythmias, and sudden death. CIRCULATION-CARDIOVASCULAR GENETICS. 2011;4(3):280–7.
IEEE
[1]
R. F. Marsman et al., “A complex double deletion in LMNA underlies progressive cardiac conduction disease, atrial arrhythmias, and sudden death,” CIRCULATION-CARDIOVASCULAR GENETICS, vol. 4, no. 3, pp. 280–287, 2011.
@article{8110382,
  abstract     = {Background: Cardiac conduction disease is a clinically and genetically heterogeneous disorder characterized by defects in electrical impulse generation and conduction and is associated with sudden cardiac death. 
Methods and Results: We studied a 4-generation family with autosomal dominant progressive cardiac conduction disease, including atrioventricular conduction block and sinus bradycardia, atrial arrhythmias, and sudden death. Genome-wide linkage analysis mapped the disease locus to chromosome 1p22-q21. Multiplex ligation-dependent probe amplification analysis of the LMNA gene, which encodes the nuclear-envelope protein lamin A/C, revealed a novel gene rearrangement involving a 24-bp inversion flanked by a 3.8-kb deletion upstream and a 7.8-kb deletion downstream. The presence of short inverted sequence homologies at the breakpoint junctions suggested a mutational event involving serial replication slippage in trans during DNA replication. 
Conclusions: We identified for the first time a complex LMNA gene rearrangement involving a double deletion in a 4-generation Dutch family with progressive conduction system disease. Our findings underscore the fact that if conventional polymerase chain reaction-based direct sequencing approaches for LMNA analysis are negative in suggestive pedigrees, mutation detection techniques capable of detecting gross genomic lesions involving deletions and insertions should be considered.},
  author       = {Marsman, Roos F and Bardai, Abdenasser and Postma, Alex V and Res, Jan CJ and Koopmann, Tamara T and Beekman, Leander and van der Wal, Allard C and Pinto, Yigal M and Lekanne Deprez, Ronald H and Wilde, Arthur AM and Jordaens, Luc and Bezzina, Connie R},
  issn         = {1942-325X},
  journal      = {CIRCULATION-CARDIOVASCULAR GENETICS},
  keywords     = {gene rearrangement,LMNA conduction disease,complex deletion,MLPA,LAMIN-A/C GENE,SERIAL REPLICATION SLIPPAGE,DILATED CARDIOMYOPATHY,SYSTEM DISEASE,MUTATIONS,CHANNEL,HEART,LAMINOPATHIES,TRANSCRIPTION,METAANALYSIS},
  language     = {eng},
  number       = {3},
  pages        = {280--287},
  title        = {A complex double deletion in LMNA underlies progressive cardiac conduction disease, atrial arrhythmias, and sudden death},
  url          = {http://dx.doi.org/10.1161/CIRCGENETICS.110.959221},
  volume       = {4},
  year         = {2011},
}

Altmetric
View in Altmetric
Web of Science
Times cited: