PKP2

Gene Facts

• HGNC Symbol: PKP2 (HGNC:9024)
• HGNC Name: plakophilin 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: No aliases found
• %HI: 58.3
• pLI: 0
• LOEUF: 1.11
• Cytoband: 12p11.21
• Genomic Coordinates:

  GRCh37/hg19:	chr12:32943689-33049711
  GRCh38/hg38:	chr12:32790755-32896777

• MANE Select Transcript: NM_001005242.3 ENST00000340811.9
• Function: Regulates focal adhesion turnover resulting in changes in focal adhesion size, cell adhesion and cell spreading, potentially via transcriptional modulation of beta-integrins (PubMed:23884246). Required to maintain gingival epithelial barrier function (PubMed:34368962). Required for cardiac sodium current propagation and electrical synchrony in cardiac myocytes, via ANK3 stabilization and modulation of SCN5A/Nav1.5 localization to cell-cell junctions (By similarity). Required for the formation of... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-4631
• ClinGen Curation ID: CCID:007677
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 05/10/2023

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Arrhythmogenic right ventricular dysplasia 9

HI Evidence

• PUBMED: 15489853
  Gerull et al. (2004) directly sequenced all 14 PKP2 exons, including flanking intronic splice sequences in 120 unrelated western European probands with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). The authors identified 25 different heterozygous variants in 32 probands (insertion-deletion: 12, nonsense: 6, missense: 4, and splice site: 3). Formal segregation analyses could not be carried out because parental genotypes were not available. However, a reduced penetrance was observed in two families available for a detailed clinical and molecular analysis. Western blot analysis of a right ventricular biopsy specimen obtained from a patient did not detect the truncated PKP2 protein; however, less wild-type PKP2 than control myocardium was observed, implicating the haploinsufficiency of PKP2.
• PUBMED: 24704780
  Rasmussen et al. (2014) directly sequenced PKP2 in 71 unrelated probands with arrhythmogenic cardiomyopathy. The authors identified 10 different heterozygous variants in 12 probands. Familial occurrence of the disease was present in 58% of the families. Among 20 family members with PKP2 variants, 7 fulfilled diagnostic criteria, 5 had borderline signs of the condition, whereas 8 individuals were nonpenetrant (see Figure 1 for pedigree information). Expression studies showed that PKP2 protein was significantly reduced in tissues of individuals carrying the truncating variants.
• PUBMED: 29038103
  Pilichou et al. (2017) identified 130 kb entire gene deletions (n=5), a deletion of exon 4 (n=2), a deletion of exons 6 to 11, a duplication of 5′ untranslated region till exon 1 (n=1) of PKP2 in patients with arrhythmogenic cardiomyopathy (AC) Overall, disease penetrance was 42% in relatives undergoing familial evaluation. Among the variant carriers, men were more often affected than women (71% versus 25.5%; P=0.07) (see Figure 4).
• PUBMED: 34120153
  Smith et al. (2020) identified multiple truncating variants in PKP2, including exon 6-7 and exon 5-7, in cardiomyopathy, specifically arrhythmogenic right ventricular cardiomyopathy, patients (Supplemental Table 3).
• PUBMED: 34120153
  Dries et al. (2021) reported missense and truncating variants of PKP2 in patients with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. The authors stated that the multicohort genetic evaluation of PKP2 demonstrated the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. This multicohort study identified the PKP2 C-terminus as a potential functional domain, and truncating variants likely cause disease irrespective of transcript position. Truncating variants in PKP2 are more strongly associated with ACM phenotypes than missense variants (Table 1).
• PUBMED: 35653365
  Stava et al. (2022) reported truncating variants of PKP2 in Norwegian patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). The novel truncating variants were exon 1_2 deletion and c.2145+2T ˃A. The most common ARVC variant was the c.2146-1G˃C variant in PKP2, accounting for 28% of all ARVC variants (Table 3). In this study, 2016 patients with a family history of cardiomyopathy and no findings detected by previous Sanger sequencing were further tested by NGS.

• HI Evidence Comments: Arrhythmogenic right ventricular cardiomyopathy/dysplasia 9 (ARVC/D 9) is a familial form of cardiomyopathy caused by pathogenic variants in plakophilin-2 (PKP2); it is known to be associated with reduced penetrance. PKP2 is the most common gene associated with ACM, specifically its right dominant subform, arrhythmogenic right ventricular cardiomyopathy (ARVC). The PKP2 protein is expressed in myocardial desmosomes. Since it is difficult to obtain sufficient amounts of myocardial tissue for protein expression studies, PKP2 protein expression has been investigated in a limited number of genotyped patients. The expression studies showed that patients with truncating PKP2 variants have reduced myocardial PKP2 protein expression. Further, in vitro expression studies of PKP2 variants showed protein instability. These studies indicated that PKP2 haploinsufficiency is a part of the disease mechanism in ARVC/D. Pathogenic sequence variants and entire or partial deletions of PKP2 are reported in multiple patients with ARVC/D. The pathogenic variants in desmosomal genes, including PKP2, are mostly familial and, when de novo may disproportionately be whole gene deletions. Common variants are likely founder variants. Clinical and molecular studies in ARVC families with PKP2 variants revealed a reduced penetrance. A de novo 7.9 Mb deletion of 12p12.1p11.1, involving PKP2, was reported in a patient with ARVC (Roberts et al. (2013); PMID: 22889254). Further, a de novo deletion encompassing PKP2 was reported in an ARVC patient (van Linet et al., (2019); PMID 31386562, see Figure 1). Additional publications: PMID: 31737537: Marschall et al. (2019) identified deletion exon 10-11 of PKP2 in a patient with Arrhythmogenic right ventricular cardiomyopathy. PMID 35819174: Goudal et al (2022) reported PKP2 variant in 24.4% of arrhythmogenic cardiomyopathy with right dominant form (ACR) patients. The truncating variants were p.W290*, IVS1 ds T-G +6, IVS12 ds G-A +5, c.861delG, c.938delG, c.1887delT, and c.2036delA.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: Focal duplications of the PKP2 gene have not been reported in the literature. The genomic region is not known to vary in copy number in controls.