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A single Na(+) channel mutation causing both long-QT and Brugada syndromes
C Bezzina1, M W Veldkamp, M P van Den Berg
1Departments of Clinical Genetics , Academic Medical Center, Amsterdam, The Netherlands.
Circulation Research
|December 11, 1999
Summary
A novel SCN5A gene mutation (1795insD) causes both long-QT syndrome type 3 and Brugada syndrome, leading to sudden cardiac death, particularly nocturnal deaths, in affected families.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Electrophysiology
Background:
- SCN5A gene mutations are linked to sudden cardiac death syndromes like long-QT syndrome type 3 (LQT3) and Brugada syndrome.
- These syndromes can present with overlapping clinical and electrocardiographic features.
Purpose of the Study:
- To investigate the genetic basis of sudden death in a large family with both LQT3 and Brugada syndrome phenotypes.
- To identify the specific SCN5A mutation responsible for the observed clinical manifestations.
Main Methods:
- Genetic screening of the SCN5A gene in an 8-generation family.
- Electrocardiographic (ECG) analysis of 79 individuals with known genetic status.
- Functional characterization of the identified mutation using Xenopus oocyte expression systems.
Main Results:
- A 3-nucleotide insertion (TGA) at position 5537 in SCN5A (1795insD) was identified in all affected family members.
- Affected individuals exhibited prolonged PR, QRS, and QT intervals, along with ST segment elevation.
- The 1795insD mutation altered channel gating properties, reducing sodium current during action potential upstroke.
Conclusions:
- LQT3 and Brugada syndrome can be allelic disorders arising from the same SCN5A mutation.
- The 1795insD mutation in SCN5A is a likely cause of both syndromes and associated sudden cardiac death.
- This finding highlights the genetic overlap between distinct cardiac channelopathies.