What is the clinical evidence from this study?

Study design: Observational. Population: Paediatric arrhythmogenic cardiomyopathies (n=57). Intervention: Pathogenic variants in PKP2, DSP, and gene-elusive vs. Between-genotype comparison. Primary outcome: Phenotype distribution and adverse clinical outcomes.

What question did this study set out to answer?

This study aims to explore genotype-phenotype correlations in children with arrhythmogenic cardiomyopathies.

March 21, 2026

PO07 Genotype–phenotype correlations in paediatric arrhythmogenic cardiomyopathies

Key Result

Biallelic DSP pathogenic variants in paediatric arrhythmogenic cardiomyopathies were associated with higher rates of heart transplantation (67%) and death (P=0.0015) compared to other genotypes.

Key Points

This study aims to explore genotype-phenotype correlations in children with arrhythmogenic cardiomyopathies.
Retrospective analysis of demographic and clinical data in 57 children with ACMs
Comparison of patients with different genetic variants (PKP2, DSP, gene-elusive)
Stratification of patients into genetic groups to assess phenotype diversity
Significant phenotype variation across different genotype groups (p<0.05)
All PKP2 and homozygotes presented with arrhythmogenic right ventricle cardiomyopathy
DSP variants primarily manifested as dilated cardiomyopathy, with 100% in biallelic cases
Gene-elusive patients had a diverse distribution among different cardiomyopathy types
Earlier diagnosis observed in DSP carriers compared to gene-elusive and PKP2 cases

Study Design

Type

Observational (n=57)

Structured PICO

Do pathogenic variants in PKP2 or DSP compared to gene-elusive ACMs affect phenotype expression and clinical outcomes in children?

Population

57 children with a definitive arrhythmogenic cardiomyopathy (ACM) diagnosis, including PKP2 (n=9), DSP (n=12), and gene-elusive (n=36) variants.

Intervention

Pathogenic variants in plakophilin (PKP2) or desmoplakin (DSP)

Comparator

Gene-elusive ACMs and comparison between genetic groups

Outcome

Phenotype distribution, age-related parameters, and adverse clinical outcomes (heart transplantation, death, ventricular arrhythmias, cardiac arrest, atrial arrhythmias)hard clinical

Genotype-driven risk stratification is crucial in paediatric arrhythmogenic cardiomyopathies, as biallelic DSP variants are associated with earlier onset and more severe ventricular disease.

Abstract

Abstract Background Arrhythmogenic cardiomyopathies (ACMs) in the paediatric population remain under-represented in the literature. Robust genotype–phenotype correlation data in children are lacking, limiting our ability to predict disease expression and outcomes in this vulnerable group. Purpose This study aimed to characterise and compare patients harbouring pathogenic variants in plakophilin (PKP2), desmoplakin (DSP), and gene-elusive ACMs. Methods We retrospectively analysed demographic, clinical, and outcome data in 57 children with a definitive ACMs diagnosis: PKP2 (n=9), DSP (n=12), and gene-elusive (n=36). Patients were further stratified into five genetic groups: PKP2 (n=7), PKP2 homozygotes (n=2), DSP (n=6), DSP compound heterozygous (n=6), and gene-elusive (n=36). Results Phenotype distribution varied significantly across genotype groups (p0.05). All PKP2 and PKP2 homozygotes presented with arrhythmogenic right ventricle cardiomyopathy (ARVC), while DSP variants predominantly manifested as dilated cardiomyopathy (DCM) (100% in DSP biallelic), 31% non-dilated left ventricle cardiomyopathy (NDLVC) in DSP. Gene-elusive individuals showed a balanced distribution among ARVC (36%), DCM (33%), and NDLVC (31%). Age-related parameters differed significantly (p0.05), with DSP homozygotes diagnosed earlier than PKP2 and gene-elusive cases. Time to diagnosis was also shorter in DSP carriers compared to gene-elusive patients (Table 1). Female prevalence varied between groups (p=0.029), being 100% in PKP2 carriers and only 39% in gene-elusive. Proband status differed significantly (p=0.0038), with all DSP and PKP2 biallelic being probands, compared to only 14% in PKP2 monoallelic individuals. A higher proportion of early diagnosis (at/before baseline) was observed in gene-elusive (76%) and PKP2 homozygotes (100%), though this difference was not statistically significant (p=0.058). Adverse clinical outcomes also differed by genotype. Heart transplantation was more common in DSP biallelic (67%) and DSP heterozygotes (17%) (p=0.0001), with no cases in PKP2 or gene-elusive patients. All deaths occurred in the DSP homozygous group (p=0.0015). Ventricular arrhythmias were more frequent in DSP biallelic (100%) and PKP2 (43%) (p=0.018). Cardiac arrest was observed only in PKP2 homozygotes and gene-elusive individuals (p=0.059). Atrial arrhythmias were exclusive to gene-elusive patients (28%), suggesting a distinct atrial substrate in this group. Conclusion Our findings highlight significant genotype-related differences in phenotype expression, age of onset, and clinical outcomes in paediatric ACMs. Biallelic DSP pathogenic variants are associated with earlier onset and more severe ventricular disease, whereas gene-elusive patients present with more variable phenotypes and a distinct atrial arrhythmia profile. These results support the importance of genotype-driven risk stratification in children with ACMs.

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