SCN5A-1795insD founder variant: a unique Dutch experience spanning 7 decades

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Channelopathies

Background:

• The SCN5A-1795insD founder variant is a unique genetic mutation identified in a large Dutch family.
• This variant is associated with a complex cardiac phenotype, representing one of the largest SCN5A founder families globally.
• It was the first identified SCN5A variant sufficient to cause a sodium channel overlap syndrome.

Purpose of the Study:

• To summarize 70 years of clinical experience and over two decades of research on the SCN5A-1795insD founder variant.
• To elucidate the complex phenotype associated with this SCN5A variant.
• To provide fundamental insights into SCN5A gene function and the cardiac sodium channel Nav1.5.

Main Methods:

• Extensive clinical studies of affected family members.
• Genetic analysis to identify and characterize the SCN5A variant.
• Electrophysiological and molecular studies to understand channel function.
• Longitudinal observation of the Dutch pedigree.

Main Results:

• Affected individuals exhibit features of Brugada syndrome, cardiac conduction disease, and long QT syndrome type 3.
• The SCN5A-1795insD variant demonstrates both loss-of-function and gain-of-function effects on the sodium channel.
• Significant understanding of the complex phenotype has been achieved through dedicated research.

Conclusions:

• The SCN5A-1795insD variant is a key example of a single pathogenic variant causing a spectrum of cardiac arrhythmias.
• Research has significantly advanced the understanding of SCN5A-related channelopathies and Nav1.5 function.
• This founder variant provides a unique model for studying sodium channelopathies.