Abstract
To date, a large number of mutations in SCN5A, the gene encoding the pore-forming α-subunit of the primary cardiac Na+ channel (NaV1.5), have been found in patients presenting with a wide range of ECG abnormalities and cardiac syndromes. Although these mutations all affect the same NaV1.5 channel, the associated cardiac syndromes each display distinct phenotypical and biophysical characteristics. Variable disease expressivity has also been reported, where one particular mutation in SCN5A may lead to either one particular symptom, a range of various clinical signs, or no symptoms at all, even within one single family. Additionally, disease severity may vary considerably between patients carrying the same mutation. The exact reasons are unknown, but evidence is increasing that various cardiac and non-cardiac conditions can influence the expressivity and severity of inherited SCN5A channelopathies. In this review, we provide a summary of identified disease entities caused by SCN5A mutations, and give an overview of co-morbidities and other (non)-genetic factors which may modify SCN5A channelopathies. A comprehensive knowledge of these modulatory factors is not only essential for a complete understanding of the diverse clinical phenotypes associated with SCN5A mutations, but also for successful development of effective risk stratification and (alternative) treatment paradigms.
Highlights
To date, an increasing number of mutations in SCN5A, the gene encoding the pore-forming α-subunit of the primary cardiac Na+ channel (NaV1.5), is found in patients with a wide range of electrocardiogram (ECG) abnormalities and cardiac syndromes [1,2,3]
Clinical management of SCN5A mutation-positive patients is hindered by this reduced penetrance as well as by the considerable variation in disease severity and risk of sudden cardiac death (SCD) observed in affected individuals
By performing a system genetics approach on F2 progeny arising from these two mouse strains, we showed that Tnni3k is another modulator of AV conduction [53]
Summary
An increasing number of mutations in SCN5A, the gene encoding the pore-forming α-subunit of the primary cardiac Na+ channel (NaV1.5), is found in patients with a wide range of electrocardiogram (ECG) abnormalities and cardiac syndromes [1,2,3]. SCN5A mutations underlying LQT3 are typically “gainof-function” mutations inducing various biophysical alterations The SCN5A mutations underlying MEPPC are typically gain-of-function mutations due to an increased window INa, faster recovery from inactivation and/or increased channel availability of NaV1.5 (see [16], and primary references cited therein).
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