Is Wolff-Parkinson-White (WPW) syndrome genetic?

Genetic Basis of Wolff-Parkinson-White Syndrome

WPW syndrome has a genetic component, with mutations in several genes identified as causative, most notably PRKAG2, and evidence of increased burden of rare deleterious variants in genes associated with atrial fibrillation. 1

Genetic Etiology

WPW syndrome results from the congenital presence of accessory pathways (APs) that connect the atria and ventricles, bypassing the normal AV nodal conduction system. The genetic basis of WPW varies depending on whether it occurs with or without structural heart disease:

• PRKAG2 mutations: Account for approximately 0.6% of WPW cases 1

  • Associated with a rare familial form of WPW with cardiomyopathy
  • Causes a cardiac-specific glycogenosis syndrome 2

• Other identified genetic associations:

  • MYH6 mutations: Identified in families with WPW syndrome 3
  • Rare de novo variants in genes associated with arrhythmia and cardiomyopathy:
    • ANK2, NEBL, PITX2, and PRDM16 1
  • Increased burden of rare deleterious variants in genes linked to atrial fibrillation 1

Clinical Implications of Genetic Factors

• Family screening: The European Society of Cardiology recommends ECG screening for siblings of young athletes with bifascicular block patterns 2

• Risk assessment:

  • Family history of sudden cardiac death should prompt consideration for electrophysiological study for risk stratification 2
  • Genetic testing may help identify patients at higher risk for associated conditions

• Associated conditions:

  • Ebstein's anomaly
  • Hypertrophic cardiomyopathy
  • Corrected transposition of the great arteries
  • Cardiac tumors 4

Epidemiology

• Prevalence: 0.1-0.3% in the general population 5
• Higher prevalence (0.33-0.5%) in patients with structural heart disease 2
• Incidence: Approximately 4 new cases per 100,000 people per year 4

Management Considerations Based on Genetic Factors

• Risk stratification: Patients with a family history of sudden cardiac death should be considered for electrophysiological study 2

• Treatment approach:

  • Catheter ablation is the first-line treatment for symptomatic WPW 4
  • For asymptomatic patients, risk assessment should guide management decisions 4
  • Special consideration for patients with high-risk professions or activities 2

• Long-term follow-up:

  • Patients should be evaluated with ECG at 3 months and annually during the first few years after ablation therapy 4
  • Approximately 5-10% may experience recurrence of accessory pathway conduction 4

Clinical Pearls

• Despite the genetic component, most cases of WPW occur sporadically
• Even after successful ablation of an accessory pathway, patients may remain at higher risk for atrial fibrillation compared to the general population due to underlying genetic factors 1
• The presence of WPW in a patient with structural heart disease should raise suspicion for specific genetic syndromes, particularly those involving PRKAG2 mutations

WPW syndrome represents a spectrum of genetic influences, from rare monogenic forms to more complex polygenic contributions that may affect both the development of accessory pathways and susceptibility to related arrhythmias.