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PKP2 – Brugada Syndrome

Heterozygous variants in PKP2 have been identified in eight unrelated Brugada syndrome probands (PMID:24352520, PMID:32443836, PMID:27122407, PMID:25998140). Inheritance follows an autosomal dominant pattern, but no extended cosegregation has been reported. Screening of 200 SCN5A-negative Brugada syndrome patients uncovered five PKP2 missense variants including c.548G>A (p.Ser183Asn) in five probands (PMID:24352520), while single reports described p.Ser183Asn in one BrS/AVNRT patient (PMID:25998140), a compound p.Ala159Thr+p.Gly265Glu in a SUNDS case (PMID:27122407), and p.Ser183Asn in one BrS‐diagnosed individual reclassified as arrhythmogenic cardiomyopathy (PMID:32443836). A systematic review noted limited genotype-phenotype correlation and urged cautious interpretation (PMID:27085656).

Functional assays reveal that PKP2 knockdown and BrS-associated PKP2 mutants in HL-1 cells and human iPSC-derived cardiomyocytes lead to reduced sodium current (INa) and NaV1.5 membrane localization, deficits rescued by wild-type but not mutant protein (PMID:24352520). These in vitro data support a mechanism whereby PKP2 variants impair cardiac sodium channel function. However, the small number of probands, absence of familial segregation, and limited replication constrain the clinical validity to a Limited level.

Key take-home: PKP2 variants may underlie Brugada syndrome through sodium current impairment, but further familial and population studies are required to establish pathogenicity and guide clinical testing.

References

  • Circulation • 2014 • Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype PMID:24352520
  • Genes • 2020 • Clinical and Molecular Data Define a Diagnosis of Arrhythmogenic Cardiomyopathy in a Carrier of a Brugada-Syndrome-Associated PKP2 Mutation PMID:32443836
  • Journal of forensic sciences • 2016 • Molecular Autopsy of Desmosomal Protein Plakophilin-2 in Sudden Unexplained Nocturnal Death Syndrome PMID:27122407
  • Heart rhythm • 2015 • High prevalence of concealed Brugada syndrome in patients with atrioventricular nodal reentrant tachycardia PMID:25998140
  • International journal of cardiology • 2016 • Brugada Syndrome and PKP2: Evidences and uncertainties PMID:27085656

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Eight unrelated Brugada syndrome probands with heterozygous PKP2 variants lacking cosegregation

Genetic Evidence

Limited

Five heterozygous missense variants in 200 Brugada syndrome patients ([PMID:24352520]); additional singleton cases ([PMID:32443836]; [PMID:27122407]; [PMID:25998140]); no segregation data

Functional Evidence

Moderate

PKP2 knockdown and BrS-related mutants in vitro reduce INa and channel localization, rescued by wild-type in HL-1 and human iPSC-CMs ([PMID:24352520])