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Paediatric patient with FLNC and CTNNA3 variants presenting with frequent premature ventricular contractions and systolic dysfunction: a case report

Published online by Cambridge University Press:  27 March 2026

Damla Gökçeer Akbulut Open the ORCID record for Damla Gökçeer Akbulut [Opens in a new window] ,
Helen Bornaun Open the ORCID record for Helen Bornaun [Opens in a new window] ,
Hamide Saygılı  and
Demet Tosun Open the ORCID record for Demet Tosun [Opens in a new window]
Damla Gökçeer Akbulut*
Affiliation:
Department of Pediatric Cardiology, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Türkiye
Helen Bornaun
Affiliation:
Department of Pediatric Cardiology, Kanuni Sultan Suleyman Training and Research Hospital, Türkiye
Hamide Saygılı
Affiliation:
Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, Türkiye
Demet Tosun
Affiliation:
Department of Pediatric Intensive Care Unit, Kanuni Sultan Suleyman Training and Research Hospital, Türkiye
*
Corresponding author: Damla Gökçeer Akbulut; Email: dgkceer@hotmail.com
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Abstract

We present the case of an 8-year-old male with frequent premature ventricular contractions and mild left ventricular dysfunction, who was found to carry heterozygous variants in both FLNC and CTNNA3. Medical therapy resulted in improved systolic function and reduced arrhythmia burden. This rare combination suggests a potential genotype–phenotype correlation in paediatric arrhythmogenic cardiomyopathy.

Keywords

FLNC mutationCTNNA3 mutationarrhythmogenic cardiomyopathygenetic testingchild

Information

Type
Case Report
Information
Cardiology in the Young , Volume 36 , Issue 3 , March 2026 , pp. 645 - 647
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Copyright
© The Author(s), 2026. Published by Cambridge University Press

Case report

An 8-year-old boy presented with intermittent chest pain for 3 months. Physical examination was unremarkable. Electrocardiography revealed frequent premature ventricular contractions with trigeminy (Figure 1). Twenty-four-hour Holter monitoring demonstrated a premature ventricular contraction burden of 40%. Transthoracic echocardiography revealed mild systolic dysfunction (left ventricular ejection fraction: 50%). Laboratory investigations including serum troponin and metabolic screening were normal.

Figure 1.

12-lead electrocardiogram from the patient demonstrating isolated, uniform premature ventricular contractions (PVCs) occurring in a trigeminal pattern. No signs of repolarization abnormality or ventricular hypertrophy are evident.

Initial treatment with propranolol failed to reduce the premature ventricular contraction burden. Antiarrhythmic therapy was subsequently changed to sotalol, a Class III antiarrhythmic agent, alongside an angiotensin-converting enzyme (ACE) inhibitor. This combination resulted in normalisation of systolic function (ejection fraction: 65%), and the 24-hour Holter monitoring showed a reduction in premature ventricular contraction burden from 40% to 10%.

Cardiac MRI revealed no evidence of myocardial oedema on fat-suppressed T2-weighted sequences or T2 mapping. Native T1 values and extracellular volume of the left ventricular myocardium were within normal limits. First-pass perfusion imaging showed no perfusion defects in the interventricular septum or in either ventricular wall. Left ventricular systolic function was at the lower limit of normal (ejection fraction: 51%), and right ventricular systolic function was also borderline (ejection fraction: 48%). Quantitative tissue characterisation demonstrated non-ischaemic myocardial fibrosis involving more than 3% of the left ventricular myocardium. Late gadolinium enhancement imaging revealed a subtle, mid-myocardial focal enhancement in the mid-ventricular anteroseptal segment, consistent with a non-ischaemic pattern (Figure 2).

Figure 2.

Sagittal cardiac magnetic resonance (CMR) image demonstrating normal thoracic anatomy. No myocardial oedema was observed on fat-suppressed T2-weighted sequences or T2 mapping. Quantitative tissue characterisation showed >3% non-ischaemic fibrosis of the left ventricle, with late gadolinium enhancement (LGE) in the mid-myocardial anteroseptal segment.

Genetic testing revealed variants in FLNC and CTNNA3, both implicated in arrhythmogenic cardiomyopathy.

Introduction

Arrhythmogenic cardiomyopathy is a genetically heterogeneous disorder primarily affecting the right ventricle, characterised by progressive fibrofatty myocardial replacement, ventricular arrhythmias, and an increased risk of sudden cardiac death, particularly in young individuals.Reference Mattesi, Zorzi, Corrado and Cipriani1,Reference Tadros, Miyake, Kearney, Kim and Denfield2 Although classical arrhythmogenic right ventricular dysplasia (ARVD) is predominantly linked to desmosomal gene mutations, recent studies have identified pathogenic variants in non-desmosomal genes such as FLNC (filamin C) and CTNNA3 (catenin alpha-3) that contribute to overlapping arrhythmogenic phenotypes.Reference Dong, Zhou and Zhang3,Reference Ader, De Groote and Réant4

The FLNC gene encodes filamin C, a cytoskeletal protein essential for myocardial structural integrity, and pathogenic variants have been associated with arrhythmogenic and dilated cardiomyopathies.Reference Dong, Zhou and Zhang3,Reference Alsubhi, Aldarwish and Agrawal5,Reference Baban, Alesi and Magliozzi6 CTNNA3, encoding catenin alpha-3, has also been implicated in arrhythmogenic remodelling through impaired intercellular adhesion.Reference Tadros, Miyake, Kearney, Kim and Denfield2,Reference Ader, De Groote and Réant4

While isolated variants in each gene have been described in the literature, the co-occurrence of FLNC and CTNNA3 heterozygous variants in a paediatric patient is exceedingly rare. Here, we report the case of an 8-year-old male presenting with frequent premature ventricular contractions, left ventricular dysfunction, and two concurrent heterozygous variants—FLNC c.3301G >A (p. Gly1101Ser) and CTNNA3 c.988G >A (p. Ala330Thr). This case highlights the clinical relevance of comprehensive genetic evaluation in early-onset ventricular arrhythmias and suggests potential synergistic pathogenicity of multiple non-desmosomal variants in paediatric arrhythmogenic cardiomyopathy.

Genetic analysis

Targeted single-gene mutation analysis was performed using polymerase chain reaction (PCR) and genomic DNA sequencing techniques. The test identified a heterozygous FLNC variant, c.3301G >A (p. Gly1101Ser), previously associated with cardiomyopathy phenotypes. This variant was confirmed in peripheral blood obtained from the patient.

Discussion

This case underscores the significance of evaluating genetic contributions in paediatric patients presenting with idiopathic dilated cardiomyopathy. Although truncating mutations in the FLNC gene are infrequent, they are strongly associated with life-threatening ventricular arrhythmias and sudden cardiac death.Reference Ader, De Groote and Réant4 The presence of atypical biventricular involvement may reflect overlapping cardiomyopathy phenotypes, further complicating the diagnostic approach. Timely genetic screening, multimodal imaging, and individualised management strategies are essential for improving prognosis and guiding follow-up.Reference Mattesi, Zorzi, Corrado and Cipriani1,Reference Tadros, Miyake, Kearney, Kim and Denfield2

Although FLNC variants are more commonly reported in adults, recent paediatric series have highlighted their clinical relevance. For instance, in a cohort of 500 paediatric patients, FLNC variants were reported in 14 individuals (2.8%), some of whom exhibited cardiomyopathy or arrhythmic manifestations.Reference Dong, Zhou and Zhang3,Reference Baban, Alesi and Magliozzi6 A study published in 2024 further described novel FLNC mutations in children, emphasising their potential association with dilated or mixed-type cardiomyopathy.Reference Dong, Zhou and Zhang3 Another report highlighted that FLNC-related forms of “pediatric cardiomyopathy,” while rare, represent a clinically significant subgroup.Reference Alsubhi, Aldarwish and Agrawal5,Reference Baban, Alesi and Magliozzi6

In contrast, CTNNA3 has been implicated in arrhythmogenic cardiomyopathy and ventricular arrhythmias, although existing evidence is largely derived from studies in adults or young adults.Reference Tadros, Miyake, Kearney, Kim and Denfield2 To our knowledge, there are no prior reports describing a paediatric patient presenting with this specific combination of clinical manifestations and dual FLNC–CTNNA3 heterozygous variants. Thus, this case may represent a previously unrecognised phenotype.

Conclusion

This case highlights the importance of integrating advanced cardiac imaging and genetic testing in the evaluation of paediatric patients presenting with idiopathic arrhythmias and systolic dysfunction. The identification of concurrent FLNC and CTNNA3 variants may contribute to arrhythmogenic cardiomyopathy and underscores the need for comprehensive genotype–phenotype assessment in similar clinical presentations. Further studies are needed to determine the clinical significance and long-term outcomes associated with these combined variants in paediatric populations.

Data availability statement

Data used in this study can be provided on reasonable request.

Financial support

This study did not receive financial support.

Competing interests

The authors declare that they have no conflict of interest to disclose.

Consent to participate

The informed consent form was obtained from the patient.

References

Mattesi, G, Zorzi, A, Corrado, D, Cipriani, A. Natural history of arrhythmogenic cardiomyopathy. J Clin Med 2020; 9(3): 878.CrossRefGoogle ScholarPubMed
Tadros, HJ, Miyake, CY, Kearney, DL, Kim, JJ, Denfield, SW. The many faces of arrhythmogenic cardiomyopathy: an overview. Appl Clin Genet 2023; 16: 181–203. DOI: 10.2147/TACG.S383446.CrossRefGoogle ScholarPubMed
Dong, R, Zhou, X, Zhang, H, et al. Novel FLNC variants in pediatric cardiomyopathy: an insight into disease mechanisms. Hum Genomics 2024; 18: 118. DOI: 10.1186/s40246-024-00683-9.CrossRefGoogle ScholarPubMed
Ader, F, De Groote, P, Réant, P, et al. FLNC pathogenic variants in patients with cardiomyopathies: prevalence and genotype-phenotype correlations. Clin Genet 2019; 96(4): 317–329. DOI: 10.1111/cge.13594.CrossRefGoogle ScholarPubMed
Alsubhi, A, Aldarwish, M, Agrawal, PB, et al. A child with dilated cardiomyopathy and homozygous splice site variant in FLNC gene. Mol Genet Metab Rep 2023; 38: 101027. DOI: 10.1016/j.ymgmr.2023.101027.Google ScholarPubMed
Baban, A, Alesi, V, Magliozzi, M, et al. Cardiovascular involvement in pediatric FLNC variants: a case series of fourteen patients. J Cardiovasc Dev Dis 2022; 9(10): 332. DOI: 10.3390/jcdd9100332.Google ScholarPubMed
Figure 0

Figure 1. 12-lead electrocardiogram from the patient demonstrating isolated, uniform premature ventricular contractions (PVCs) occurring in a trigeminal pattern. No signs of repolarization abnormality or ventricular hypertrophy are evident.

Figure 1

Figure 2. Sagittal cardiac magnetic resonance (CMR) image demonstrating normal thoracic anatomy. No myocardial oedema was observed on fat-suppressed T2-weighted sequences or T2 mapping. Quantitative tissue characterisation showed >3% non-ischaemic fibrosis of the left ventricle, with late gadolinium enhancement (LGE) in the mid-myocardial anteroseptal segment.