Systematic analysis of SCN5A variants associated with inherited cardiac diseases.
作者信息
Hermida Alexis, Jedraszak Guillaume, Ader Flavie, Denjoy Isabelle, Fressart Véronique, Maury Phillipe, Beyls Christophe, Bloch Adrien, Clerici Gaël, Daire Elise, Defaye Pascal, Dupin-Deguine Delphine, Garçon Loic, Klug Didier, Ginglinger Emmanuelle, Hermida Jean-Sylvain, Jesel Laurence, Khraiche Diala, Kubala Maciej, Lacotte Jérôme, Laredo Mikael, Leenhardt Antoine, Le Guillou Xavier, Lesaffre Francois, Maltret Alice, Magnin-Poull Isabelle, Marijon Eloi, Nambot Sophie, Neyroud Nathalie, Ninni Sandro, Palmyre Aurélien, Pasquie Jean Luc, Proukhnitzky Julie, Reant Patricia, Richard Pascale, Rollin Anne, Rooryck Caroline, Sacher Frédéric, Schaefer Elise, Vernier Agathe, Winum Pierre-François, Wahbi Karim, Waintraub Xavier, Waldmann Victor, Weber Sacha, Zouaghi Amir, Charron Philippe, Extramiana Fabrice, Gandjbakhch Estelle
机构信息
Cardiology, Arrhythmia, and Cardiac Stimulation Service, Amiens-Picardie University Hospital, Amiens, France; EA4666 HEMATIM, University of Picardie-Jules Verne, Amiens, France; Institute of Cardiology and ICAN Institute for Cardiometabolism and Nutrition, APHP, Pitié-Salpêtrière Hospital, Paris, France; Department of Genetics, Department of Cardiology, and Referral center for hereditary cardiac diseases, APHP, Pitié-Salpêtrière Hospital, Paris, France.
EA4666 HEMATIM, University of Picardie-Jules Verne, Amiens, France; Molecular Genetics Laboratory, Amiens-Picardie University Hospital, Amiens, France.
出版信息
Heart Rhythm. 2025 Mar;22(3):844-851. doi: 10.1016/j.hrthm.2024.08.018. Epub 2024 Aug 10.
BACKGROUND
SCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes or pleiotropy, which have not been systematically described. In addition, the involvement of SCN5A in dilated cardiomyopathies (DCMs) remains controversial.
OBJECTIVE
We aimed to evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and to determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers.
METHODS
The DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced with a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped.
RESULTS
The study included 170 P/LP variants found in 495 patients. Of them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, 6 with progressive cardiac conduction disease, 4 with multifocal ectopic Purkinje-related premature contractions, and 3 with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Of those, 8 were carried by 8 patients presenting with DCM with a debatable causative genotype/phenotype link.
CONCLUSION
Most P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960) if not questionable.
Zotero 插件