Arrhythmogenic Cardiomyopathy PKP2-Related: Clinical and Functional Characterization of a Pathogenic Variant Detected in Two Italian Families
Abstract
:1. Introduction
- Morphofunctional Alterations (right ventricular (RV) dilatation or wall motion abnormalities);
- Myocardium Histology (fibro-adipose replacement);
- Repolarization Abnormalities (inverted T waves in right precordial leads);
- Depolarization/Conduction Abnormalities (ε waves in the right precordial leads, prolonged QRS duration);
- Arrhythmias (ventricular tachycardia, ventricular extrasystoles);
- Family History (positive for ACM and/or SCD).
2. Case Description
3. Materials and Methods
3.1. Clinical Evaluation
3.2. Genetic Analysis
3.3. PKP2 Gene Expression in PBMCs
3.4. PKP2 Protein Expression in PBMCs
3.5. Statistical Analysis
4. Results
4.1. Molecular Results
- PVS1: Null variant in a gene where LOF is a known mechanism of disease;
- PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium;
- PP1: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.
4.2. Clinical Characterization
4.3. Functional Characterization
5. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AMI | Acute Myocardial Infarction |
ACMG | American College of Medical Genetics and Genomics |
ACM | Arrhythmogenic Cardiomyopathy |
DCM | Dilated Cardiomyopathy |
EKG | Electrocardiogram |
ICD | Implantable Cardioverter Defibrillator |
ILR | Implantable loop recorder |
NGS | Next Generation Sequencing |
PBMCs | Peripheral Blood Mononuclear Cells |
PKP2 | Plakophilin-2 |
PSVT | Paroxysmal Supraventricular Tachycardia |
RV | Right Ventricle |
RT-qPCR | Quantitative RT-polymerase chain reaction |
SCD | Sudden Cardiac Death |
WT | Wild-Type |
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Fam; pt | Sex | Symptoms | ECG Findings | Morphofunctional Abnormalities | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Palpitations | Syncope | Low QRS | ε-Waves | Negative | Negative | RV | RV | RV | LV | LGE | ||
Voltage | T Waves in Leads | T Waves Beyond Lead V3 | Dilation | Dysfunction | Regional | Dilation | ||||||
in Limb Leads | V1-V2/V3 | WMA | ||||||||||
Fam 2; III:3 | F | yes | / | / | yes | yes | yes | yes | yes | bulging | / | no |
Fam 2; III:1 | F | yes | yes | / | / | yes | yes | / | yes | bulging | / | yes |
Fam 1; II:2 | M | yes | / | yes | yes | / | / | yes | yes | bulging | yes | no |
Fam 2; IV:7 | F | / | / | yes | / | / | / | / | / | / | / | no |
Fam 2; IV:6 | M | / | / | / | / | / | / | / | / | / | / | no |
Fam 2; IV:1 | M | / | / | / | / | / | / | / | / | / | / | no |
Fam 2; IV:4 | M | / | / | / | / | / | / | / | / | / | / | no |
Fam 2; IV:2 | M | / | / | / | / | / | / | / | yes | bulging | / | no |
Fam 1; III:1 | M | / | / | / | / | / | / | yes | yes | / | yes | yes |
Fam 1; III:2 | M | / | / | / | / | / | / | / | / | / | / | no |
Fam 1; III:3 | M | / | / | / | / | / | yes | / | / | / | / | yes |
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Marchionni, E.; Lomuscio, S.; Latini, A.; Murdocca, M.; Romeo, F.; Crescenzi, C.; Calò, L.; Novelli, G.; Mango, R.; Sangiuolo, F. Arrhythmogenic Cardiomyopathy PKP2-Related: Clinical and Functional Characterization of a Pathogenic Variant Detected in Two Italian Families. Genes 2025, 16, 419. https://doi.org/10.3390/genes16040419
Marchionni E, Lomuscio S, Latini A, Murdocca M, Romeo F, Crescenzi C, Calò L, Novelli G, Mango R, Sangiuolo F. Arrhythmogenic Cardiomyopathy PKP2-Related: Clinical and Functional Characterization of a Pathogenic Variant Detected in Two Italian Families. Genes. 2025; 16(4):419. https://doi.org/10.3390/genes16040419
Chicago/Turabian StyleMarchionni, Enrica, Sonia Lomuscio, Andrea Latini, Michela Murdocca, Fabiana Romeo, Cinzia Crescenzi, Leonardo Calò, Giuseppe Novelli, Ruggiero Mango, and Federica Sangiuolo. 2025. "Arrhythmogenic Cardiomyopathy PKP2-Related: Clinical and Functional Characterization of a Pathogenic Variant Detected in Two Italian Families" Genes 16, no. 4: 419. https://doi.org/10.3390/genes16040419
APA StyleMarchionni, E., Lomuscio, S., Latini, A., Murdocca, M., Romeo, F., Crescenzi, C., Calò, L., Novelli, G., Mango, R., & Sangiuolo, F. (2025). Arrhythmogenic Cardiomyopathy PKP2-Related: Clinical and Functional Characterization of a Pathogenic Variant Detected in Two Italian Families. Genes, 16(4), 419. https://doi.org/10.3390/genes16040419