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Cardiac conduction defects associate with mutations in SCN5A

Nature Genetics volume 23, pages 20–21 (1999) Cite this article

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Progressive cardiac conduction defect (PCCD), also called Lenegre1 or Lev2 disease, is one of the most common cardiac conduction disturbances. It is characterized by progressive alteration of cardiac conduction through the His-Purkinje system with right or left bundle branch block and widening of QRS complexes, leading to complete atrio-ventricular block and causing syncope and sudden death. It represents the major cause for pacemaker implantation in the world (0.15 implantations per 1,000 inhabitants per year in developed countries). Of unknown origin, PCCD is considered a primary degenerative disease or an exaggerated ageing process with sclerosis affecting only the conducting tissue. Several familial cases with right bundle branch have been reported. Although a first locus (HBN1) has been mapped to chromosome 19q13.3 (refs 3,4), no gene has yet been identified for isolated cardiac conduction defect. Here we report a mutation in the gene encoding the cardiac-specific sodium channel (SCN5A) that segregates with PCCD in an autosomal dominant manner in a large French family. In a smaller Dutch family, another SCN5A mutation co-segregates with a familial non-progressive conduction defect. This is the first gene identified whose mutation causes an isolated cardiac conduction defect.

Regarding the degenerative aspect of the conduction defect identified in the French family, it should be noted that multiple factors are involved in the conduction of the cardiac impulse12,13. In young individuals, the impaired sodium channel did not cause severe conduction defect. With ageing, increases in fibrosis in association with the genetic defect may impair the propagation of the impulse through the conducting system and reveal the PCCD phenotype. It should be stressed that although Lenegre and Lev attributed the PCCD to progressive fibrosis with ageing, fibrosis without PCCD is also observed in elderly patients14. The Dutch family with the mutation that introduces a premature stop codon presented with a congenital conduction defect from birth. This suggests that depending on the consequence of a mutation on the sodium channel characteristics, the resulting phenotype may be progressive or immediate.

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Figure 1: Pedigrees and symptoms of the PCCD families.
BERJAYA
Figure 2: Identification of SCN5A mutations in the two families.
BERJAYA

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Acknowledgements

We thank C. Fruchet and M.-J. Louërat for assistance and the families for participation. This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale to H.L.M. and D.E. (PROGRES 4P009D); the Programme Hospitalier de Recherche Clinique (PHRC 1997) to H.L.M.; the Dutch Heart Foundation (NHS 95.014) to A.A.M.W; and the Inter-University Cardiology Institute, The Netherlands.

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Author notes

  1. Jean-Jacques Schott, Connie Alshinawi and Florence Kyndt: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires, INSERM CJF96-01, Hôpital Hotel-Dieu, and Department of Cardiology, Hôpital G&R Laennec, Nantes, France

    Jean-Jacques Schott, Florence Kyndt, Vincent Probst, Denis Escande & Hervé Le Marec

  2. Department of Pediatric Cardiology, Experimental and Molecular Cardiology, University Hospital, Utrecht, The Netherlands

    Connie Alshinawi & Arthur A.M. Wilde

  3. Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, University Hospital, Utrecht, The Netherlands

    Connie Alshinawi, Miriam Hulsbeek & Marcel M.A.M. Mannens

  4. Department of Pediatric Cardiology, University Hospital, Utrecht, The Netherlands

    Theo M. Hoorntje

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  1. Jean-Jacques Schott
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  2. Connie Alshinawi
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  4. Vincent Probst
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Correspondence to Hervé Le Marec.

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Schott, JJ., Alshinawi, C., Kyndt, F. et al. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet 23, 20–21 (1999). https://doi.org/10.1038/12618

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