PRKAG2 – Wolff-Parkinson-White Syndrome

The PRKAG2 gene encodes the γ2 regulatory subunit of AMP-activated protein kinase (AMPK). Pathogenic missense variants in PRKAG2 cause an autosomal dominant Wolff-Parkinson-White (WPW) syndrome characterized by ventricular pre-excitation, conduction defects, and cardiac hypertrophy. Genetic linkage in two large pedigrees (23 in Family 1 and 8 in Family 2; total 31 affected members) demonstrated co-segregation of the recurrent c.905G>A (p.Arg302Gln) variant with WPW ([PMID:11407343]). Subsequent reports have identified PRKAG2 missense variants in over 20 additional individuals across diverse familial and sporadic cases ([PMID:31720784]; [PMID:36426223]).

Inheritance of PRKAG2-related WPW follows an autosomal dominant pattern with high penetrance. Segregation analysis in the index families confirmed variant transmission in 31 affected relatives ([PMID:11407343]). Case series have described recurrent variants including c.905G>A (p.Arg302Gln) in multiple populations, and novel variants such as c.911C>G (p.Ala304Gly) in a father-son pair presenting with atrial fibrillation and ventricular fibrillation cardiac arrest ([PMID:31720784]).

Mechanistic studies reveal that PRKAG2 mutations confer constitutive AMPK activation leading to myocardial glycogen accumulation without myofibrillar disarray. Yeast Snf4 assays and cardiac histopathology confirmed a metabolic storage cardiomyopathy distinct from sarcomeric hypertrophic cardiomyopathy ([PMID:11827995]). Cardiac-restricted transgenic mice expressing R302Q recapitulate ventricular pre-excitation, accessory pathway formation, conduction block, and hypertrophy with reduced AMPK activity and excessive glycogen deposition ([PMID:15611370]).

Some WPW pedigrees in North African families showed no PRKAG2 coding variants, underscoring genetic heterogeneity in pre-excitation syndromes ([PMID:20561859]).

Collectively, robust segregation in multiple pedigrees, recurrent pathogenic missense variants, and concordant functional data across yeast, murine, and cellular models establish a definitive gene–disease relationship between PRKAG2 and WPW syndrome. Clinical sequencing of PRKAG2 should be prioritized in patients with autosomal dominant WPW and unexplained cardiac hypertrophy.

Key take-home: PRKAG2 variant screening is essential for accurate diagnosis and management of WPW syndrome with hypertrophy.

References

• The New England journal of medicine • 2001 • Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. PMID:11407343
• The Journal of clinical investigation • 2002 • Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. PMID:11827995
• Circulation • 2005 • Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome. PMID:15611370
• Pediatric cardiology • 2020 • Novel PRKAG2 Variant Manifesting with a Cardiac Arrest in a Child. PMID:31720784
• Heart & lung : the journal of critical care • 2010 • Clinical and genetic investigation of pediatric cases of Wolff-Parkinson-White syndrome in Tunisian families. PMID:20561859
• Frontiers in cardiovascular medicine • 2022 • Case report: Genomic screening for inherited cardiac conditions in Ecuadorian mestizo relatives: Improving familial diagnose. PMID:36426223

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