Is Wolff-Parkinson-White Syndrome Hereditary?
WPW syndrome can be hereditary in rare cases, but the vast majority of cases (>95%) occur sporadically without a clear genetic inheritance pattern. 1, 2
Genetic Forms of WPW
PRKAG2-Related Familial WPW
- A specific hereditary form exists caused by mutations in the PRKAG2 gene, which encodes the gamma2 regulatory subunit of AMP-activated protein kinase. 3
- This familial form follows an autosomal dominant inheritance pattern, meaning affected individuals have a 50% chance of passing the condition to each child. 3
- The PRKAG2-related WPW is associated with cardiac hypertrophy and glycogen storage cardiomyopathy, distinguishing it from typical isolated WPW. 4, 3
- This genetic form accounts for less than 1% of all WPW cases (only 0.6% in one large genetic study). 2
Other Genetic Associations
- Recent genetic studies have identified rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, PRDM16) in some WPW patients. 2
- There is an increased burden of rare deleterious variants in genes linked to atrial fibrillation in WPW patients compared to controls, suggesting some genetic susceptibility. 2
- Familial occurrence has been documented in only seven instances in the literature prior to 1982, with one additional family showing autosomal dominant inheritance affecting multiple siblings. 5
Clinical Implications for Family Screening
When to Consider Genetic Testing
- Obtain ECGs in siblings of young athletes with WPW or bifascicular block patterns to screen for familial forms. 4
- Family history assessment should focus on pre-excitation in first-degree relatives, sudden cardiac death in young family members, and cardiomyopathy. 6
- Echocardiography is essential to identify PRKAG2-related familial WPW, which presents with cardiac hypertrophy and glycogen storage features. 4, 6
Risk Stratification in Familial Cases
- Familial WPW is associated with a high incidence of sudden death, making risk stratification particularly important in these rare cases. 6
- Electrophysiological study for risk stratification should be reserved for selected patients with a family history of sudden cardiac death. 4
Sporadic WPW (The Majority)
- Most WPW cases (>95%) occur sporadically due to congenital presence of accessory pathways without identifiable genetic mutations. 1, 7
- The anatomical substrate is a direct muscular connection between atria and ventricles that forms during cardiac development, typically without hereditary basis. 4
- Prevalence in the general population is 0.1-0.3%, with most cases representing isolated congenital anomalies rather than inherited conditions. 4, 1