SCN5A – Progressive Familial Heart Block Type 1A

Progressive familial heart block type 1A (Lenègre disease) is an autosomal dominant cardiac conduction disorder characterized by age-dependent slowing of impulse propagation in the His–Purkinje system. The SCN5A gene encodes the Na+ channel α-subunit (Nav1.5), which is critical for rapid myocardial conduction. Variants in SCN5A have been implicated in a spectrum of arrhythmic disorders, including Lenègre disease. The rigorous delineation of genotype–phenotype relationships underpins the value of SCN5A sequencing in affected families and guides management of conduction system disease.

Genetic Evidence

A canonical splice-site variant, c.3960+1G>A, was identified in a large French pedigree and shown to segregate with conduction defects (PMID:12598077). Among 65 members at risk, 25 individuals carrying c.3960+1G>A exhibited progressive PR and QRS prolongation with age, confirming autosomal dominant inheritance and variant segregation. No other SCN5A alleles were reported in this cohort, defining a narrow variant spectrum for Lenègre disease.

Functional Evidence

In vitro analyses demonstrate that c.3960+1G>A leads to exon 22 skipping and complete loss of function of the affected allele, while preserving normal channel trafficking (PMID:12598077). These findings support a haploinsufficiency mechanism whereby a 50% reduction in Nav1.5 current, in combination with age-related fibrosis, results in progressive impairment of conduction velocity.

Conflicting Evidence

No studies have refuted the association between SCN5A loss-of-function variants and Lenègre disease, and no alternative genetic etiologies were identified in the original pedigree.

Integration and Clinical Utility

The concordance of strong segregation and functional loss-of-function data establishes SCN5A c.3960+1G>A as a pathogenic driver of autosomal dominant Lenègre disease. Clinical testing for SCN5A splice-site and loss-of-function variants should be prioritized in families with unexplained conduction slowing. Early genetic diagnosis enables timely device implantation and tailored surveillance.

Key Take-home: Haploinsufficiency of SCN5A underlies progressive familial heart block type 1A, and targeted genetic testing informs risk stratification and management.

References

• Journal of the American College of Cardiology • 2003 • Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease PMID:12598077

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