Familial dilated cardiomyopathy associated with large TTN deletions and a novel PKP2 variant: A case for digenic inheritance

Q: What is the clinical evidence from this study?

Study design: Case Report. Population: Familial dilated cardiomyopathy (n=1). Intervention: Next-generation sequencing.

Agata Krawczyk-Ożóg; Ida Szataniak; Barbara Zdzierak; Magdalena Zawada; Artur Dziewierz; Stanisław Bartuś; Renata Rajtar-Salwa

doi:10.33963/v.phj.113032

June 5, 2026Kardiologia PolskaOpen Access

Familial dilated cardiomyopathy associated with large TTN deletions and a novel PKP2 variant: A case for digenic inheritance

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Key result

Pathogenic TTN deletions and a novel PKP2 variant suggest digenic inheritance in familial DCM.

n=1

Key Points

To determine the genetic basis of severe, early-onset familial dilated cardiomyopathy in a multi-generational family presenting with heart failure.
Evaluated a 47-year-old proband and screened family members using transthoracic echocardiography, Holter monitoring, and cardiac magnetic resonance imaging.
Conducted genetic screening using a next-generation sequencing panel targeting 15 cardiomyopathy-associated genes.
Detected a novel missense variant of uncertain significance in plakophilin-2 (PKP2), c.891C>A p.(Ser297Arg), supporting a digenic 'two-hit' model where desmosomal and sarcomeric disruptions synergize to worsen disease severity.
Cardiac evaluation revealed left ventricular ejection fractions of 40% in the 47-year-old proband, 48% in her 23-year-old daughter, and 50% in her 20-year-old daughter.

Study Design

Type

Case Report (n=1)

Structured PICO

P

Population

A 47-year-old woman with familial dilated cardiomyopathy (LVEF 40%) and a strong family history of early-onset heart failure.

I

Intervention

Genetic testing using a next-generation sequencing panel of 15 cardiomyopathy-associated genes.

O

Outcome

Identification of genetic variants responsible for the familial dilated cardiomyopathy phenotype.

This case demonstrates that severe, early-onset familial dilated cardiomyopathy may be driven by digenic inheritance, specifically the combination of TTN deletions and a PKP2 variant.

Limitations

Cascade family screening is planned but not yet completed to confirm the digenic inheritance hypothesis.

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Implication

Draft 2: Highlights the potential for complex multigenic drivers in familial dilated cardiomyopathy;.

Abstract

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Discussion

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Cite This Study

Krawczyk-Ożóg et al. (2026) conducted a case report in Familial dilated cardiomyopathy (n=1). Next-generation sequencing was evaluated. Genetic testing of a 47-year-old woman with familial dilated cardiomyopathy revealed two large pathogenic TTN deletions and a novel PKP2 variant, suggesting a digenic inheritance model.

synapsesocial.com/papers/6a3c2356d15afadd906f9fea https://doi.org/10.33963/v.phj.113032

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Familial dilated cardiomyopathy associated with large TTN deletions and a novel PKP2 variant: A case for digenic inheritance

Key Points

Study Design

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Familial dilated cardiomyopathy associated with large TTN deletions and a novel PKP2 variant: A case for digenic inheritance

Key Points

Study Design

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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