Identification of a SCN5A founder mutation causing sudden death, Brugada syndrome, and conduction blocks in Southern Italy.
Adult
Atrioventricular Block
/ epidemiology
Brugada Syndrome
/ epidemiology
Death, Sudden, Cardiac
/ epidemiology
Electrocardiography
Female
Follow-Up Studies
Genotype
Humans
Incidence
Italy
/ epidemiology
Male
Middle Aged
Mutation
NAV1.5 Voltage-Gated Sodium Channel
/ genetics
Pedigree
Phenotype
Retrospective Studies
Young Adult
Arrhythmogenic diseases
Brugada syndrome
Cardiac conduction defects
Founder mutations
Sudden cardiac death
Journal
Heart rhythm
ISSN: 1556-3871
Titre abrégé: Heart Rhythm
Pays: United States
ID NLM: 101200317
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
12
02
2021
revised:
29
06
2021
accepted:
02
07
2021
pubmed:
11
7
2021
medline:
15
2
2022
entrez:
10
7
2021
Statut:
ppublish
Résumé
The genetic architecture of Brugada syndrome (BrS) is emerging as an increasingly complex area of investigation. The identification of genetically homogeneous populations can provide mechanistic insights and improve genotype-phenotype correlation. To characterize and define the clinical implications of a novel BrS founder mutation. Using a haplotype-based approach we investigated whether 2 SCN5A genetic variants could derive from founder events. Single nucleotide polymorphisms were genotyped in 201 subjects, haplotypes reconstructed, and mutational age estimated. Clinical phenotypes and historical records were collected. A SCN5A variant (c.3352C>T; p.Gln1118Ter) was identified in 3 probands with BrS originating from south Italy. The same mutation was identified in a proband from central Italy and in 1 U.S. resident subject with Italian ancestry. The 5 individuals carried a common core haplotype, whose frequency was extremely low in local noncarrier probands and in population controls (0%-6.06%). The clinical presentation included multigenerational dominant transmission of Brugada electrocardiographic pattern, high incidence of sudden cardiac death (SCD), and cardiac conduction defects (CCD). We reconstructed 7-generation pedigrees with common geographic origin. Variant's age estimates suggested that origin of the p.Gln1118Ter dates back 76 generations (95% confidence interval: 28-200). A second SCN5A variant (c.5350G>A; p.Glu1784Lys) identified in the region did not show similar founder signal. p.Gln1118Ter is a novel BrS/CCD/SCD founder mutation. We illustrate how these findings provide insights on the inheritance patterns and phenotypes associated with SCN5A mutation.
Sections du résumé
BACKGROUND
The genetic architecture of Brugada syndrome (BrS) is emerging as an increasingly complex area of investigation. The identification of genetically homogeneous populations can provide mechanistic insights and improve genotype-phenotype correlation.
OBJECTIVE
To characterize and define the clinical implications of a novel BrS founder mutation. Using a haplotype-based approach we investigated whether 2 SCN5A genetic variants could derive from founder events.
METHODS
Single nucleotide polymorphisms were genotyped in 201 subjects, haplotypes reconstructed, and mutational age estimated. Clinical phenotypes and historical records were collected.
RESULTS
A SCN5A variant (c.3352C>T; p.Gln1118Ter) was identified in 3 probands with BrS originating from south Italy. The same mutation was identified in a proband from central Italy and in 1 U.S. resident subject with Italian ancestry. The 5 individuals carried a common core haplotype, whose frequency was extremely low in local noncarrier probands and in population controls (0%-6.06%). The clinical presentation included multigenerational dominant transmission of Brugada electrocardiographic pattern, high incidence of sudden cardiac death (SCD), and cardiac conduction defects (CCD). We reconstructed 7-generation pedigrees with common geographic origin. Variant's age estimates suggested that origin of the p.Gln1118Ter dates back 76 generations (95% confidence interval: 28-200). A second SCN5A variant (c.5350G>A; p.Glu1784Lys) identified in the region did not show similar founder signal.
CONCLUSION
p.Gln1118Ter is a novel BrS/CCD/SCD founder mutation. We illustrate how these findings provide insights on the inheritance patterns and phenotypes associated with SCN5A mutation.
Identifiants
pubmed: 34245912
pii: S1547-5271(21)01861-0
doi: 10.1016/j.hrthm.2021.07.003
pii:
doi:
Substances chimiques
NAV1.5 Voltage-Gated Sodium Channel
0
SCN5A protein, human
0
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1698-1706Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.