Analysis of clinical characteristics of three patients with arrhythmogenic cardiomyopathy carrying novel pathogenic PKP2 variants

doi:10.3969/j.issn.1674-8115.2026.07.011

Abstract

Abstract:

Objective ·To report newly discovered pathogenic variants of the PKP2 gene in the Chinese population and analyze their association with the clinical phenotype of arrhythmogenic cardiomyopathy (ACM). Methods ·Clinical data, including genetic test results and imaging features, were collected from 251 Chinese patients with unexplained cardiomyopathy. All detected rare variants were analyzed by whole-exome sequencing and confirmed by Sanger sequencing. The clinical phenotypes of patients carrying PKP2 variants were analyzed. Results ·Eight patients were diagnosed with arrhythmogenic cardiomyopathy, among whom 3 (37.5%) carried novel PKP2 variants in the Chinese population. Among the three variants, the missense variant c.1256T>C (p.Leu419Ser) was associated with left ventricular involvement, the missense variant c.2264T>C (p.Leu755Ser) was associated with right ventricular involvement, and the splice-site variant c.2167+1G>C was associated with biventricular involvement and increased susceptibility to ventricular tachycardia. All three patients presented with arrhythmias, and the mean age at disease onset was (23.3±10.5) years. Conclusion ·The novel pathogenic PKP2 variants identified in Chinese population expand the variant spectrum of the PKP2 gene. Key differences in ventricular involvement patterns (univentricular or biventricular) and susceptibility to ventricular tachycardia are revealed between gain-of-function (missense variants) and loss-of-function (splicing variant) mutations of the PKP2 gene.

Key words: PKP2, arrhythmogenic cardiomyopathy (ACM), genotype, clinical phenotype

CLC Number:

R542.2

Ni Luyan, Wu Chen, Tao Zhengyu, Wang Xiaoning, Zhang Zhixuan, Dong Jiawei, Jiang Meng. Analysis of clinical characteristics of three patients with arrhythmogenic cardiomyopathy carrying novel pathogenic PKP2 variants[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(7): 928-937.

Figures/Tables 10

Fig 1 Sanger sequencing results (A) and pedigree chart (B) of Case 1

Fig 2 Sanger sequencing results (A) and pedigree chart (B) of Case 2

Fig 3 Sanger sequencing results (A) and pedigree chart (B) of Case 3

Fig 4 Species conservation analysis of missense variants

Fig 5 Hydrophobicity of amino acids in the wild-type (A) and p.Leu419Ser-variation (B) PKP2 gene

Fig 6 Electrostatic potentials of the wild-type (A) and p.Leu419Ser-variation (B) PKP2 gene

Fig 7 Hydrogen bonds of amino acid at position 419 in the wild-type (A) and p.Leu419Ser-variation (B) PKP2 gene

Fig 8 Electrocardiogram(A), UCG (B/C), and CMR(D-G) findings in Case 1

Fig 9 Electrocardiogram (A) and CMR (B-E) findings in Case 2

Fig 10 UCG (A), electrocardiogram (B/C), and CMR (D-G) findings in Case 3

TrendMD

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