A human MYBPC3 mutation appearing about 10 centuries ago results in a hypertrophic cardiomyopathy with delayed onset, moderate evolution but with a risk of sudden death.

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Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_21010160EA4C
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
A human MYBPC3 mutation appearing about 10 centuries ago results in a hypertrophic cardiomyopathy with delayed onset, moderate evolution but with a risk of sudden death.
Périodique
BMC Medical Genetics
Auteur(s)
Teirlinck C.H., Senni F., Malti R.E., Majoor-Krakauer D., Fellmann F., Millat G., André-Fouët X., Pernot F., Stumpf M., Boutarin J., Bouvagnet P.
ISSN
1471-2350 (Electronic)
ISSN-L
1471-2350
Statut éditorial
Publié
Date de publication
2012
Volume
13
Numéro
105
Pages
1-9
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: epublish. PDF type: Research article
Résumé
BACKGROUND: Hypertrophic Cardiomyopathy (HCM) is a genetically heterogeneous disease. One specific mutation in the MYBPC3 gene is highly prevalent in center east of France giving an opportunity to define the clinical profile of this specific mutation.
METHODS: HCM probands were screened for mutation in the MYH7, MYBPC3, TNNT2 and TNNI3 genes. Carriers of the MYBPC3 IVS20-2A>G mutation were genotyped with 8 microsatellites flanking this gene. The age of this MYBPC3 mutation was inferred with the software ESTIAGE. The age at first symptom, diagnosis, first complication, first severe complication and the rate of sudden death were compared between carriers of the IVS20-2 mutation (group A) and carriers of all other mutations (group B) using time to event curves and log rank test.
RESULTS: Out of 107 HCM probands, 45 had a single heterozygous mutation in one of the 4 tested sarcomeric genes including 9 patients with the MYBPC3 IVS20-2A>G mutation. The IVS20-2 mutation in these 9 patients and their 25 mutation carrier relatives was embedded in a common haplotype defined after genotyping 4 polymorphic markers on each side of the MYBPC3 gene. This result supports the hypothesis of a common ancestor. Furthermore, we evaluated that the mutation occurred about 47 generations ago, approximately at the 10th century.We then compared the clinical profile of the IVS20-2 mutation carriers (group A) and the carriers of all other mutations (group B). Age at onset of symptoms was similar in the 34 group A cases and the 73 group B cases but group A cases were diagnosed on average 15 years later (log rank test p = 0.022). Age of first complication and first severe complication was delayed in group A vs group B cases but the prevalence of sudden death and age at death was similar in both groups.
CONCLUSION: A founder mutation arising at about the 10th century in the MYBPC3 gene accounts for 8.4% of all HCM in center east France and results in a cardiomyopathy starting late and evolving slowly but with an apparent risk of sudden death similar to other sarcomeric mutations.
Mots-clé
Adult, Age of Onset, Biological Evolution, Cardiomyopathy, Hypertrophic/genetics, Cardiomyopathy, Hypertrophic/pathology, Carrier Proteins/genetics, Carrier Proteins/metabolism, Death, Sudden, Female, Founder Effect, Genotype, Haplotypes, Heterozygote, Humans, Male, Middle Aged, Mutation, Risk Factors, Sarcomeres/genetics
Pubmed
Web of science
Open Access
Oui
Création de la notice
21/02/2013 18:50
Dernière modification de la notice
20/08/2019 13:57
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