Familial Dilated Cardiomyopathy Associated with a Desmoplakin Variant: A Case Report

Abbreviations

ACM, Arrhythmogenic cardiomyopathy

ARVC, Arrhythmogenic right ventricular cardiomyopathy

DCM, Dilated cardiomyopathy

DSP, Desmoplakin

LV, Left ventricular

SCD, Sudden cardiac death

VAs, Ventricular arrhythmias

INTRODUCTION

Desmoplakin (DSP) is a desmosomal protein that maintains myocardial structural integrity and normal electrical conduction by preserving intercellular coupling at the intercalated disc.¹ Pathogenic variants of DSP were first identified in Carvajal syndrome, an autosomal recessive cardiocutaneous disorder characterized by dilated cardiomyopathy (DCM) accompanied by woolly hair and palmoplantar keratoderma.² Increasing evidence highlights an association between heterozygous DSP variants and left-dominant arrhythmogenic cardiomyopathy (ACM), which is often associated with prominent left ventricular (LV) involvement, myocardial fibrosis, and ventricular arrhythmias (VAs).³ These clinical presentations underscore the phenotypic heterogeneity of DSP-related cardiomyopathy. Herein, we report the case of a family with progressive heart failure and VAs caused by a truncating DSP variant (c.448C>T; p.Arg150*), illustrating a familial DCM phenotype associated with DSP.

CASE REPORT

A 53-year-old woman with no prior medical history developed mild chest tightness and exertional dyspnea in 2019. At that time, she reported that several family members had symptoms suggestive of mild heart failure. Initial transthoracic echocardiography revealed mildly reduced LV systolic function, with an estimated ejection fraction of 40%-45%. Her blood pressure was 139/77 mmHg, and her heart rate was 96 bpm. She was prescribed bisoprolol and valsartan but did not return for follow-up until 5 years later. During the next 5 years, her symptoms progressively worsened; she experienced increasing exercise intolerance and intermittent palpitations. In May 2024, she presented to our department for further evaluation. Electrocardiography revealed sinus rhythm. Laboratory testing indicated a mildly elevated level of N-terminal pro-B-type natriuretic peptide (69.0 pmol/L). Holter monitoring over a period of 18 h and 39 min revealed 1310 ventricular ectopic beats, accounting for 1.53% of all recorded beats. Occasional short runs of nonsustained ventricular tachycardia were noted (Figure 1A). Serial echocardiography indicated progressive deterioration of LV systolic function, with the ejection fraction decreasing from 40%-45% in 2020 to 30%-35% in May 2024 (Figure 1B). The patient was prescribed guideline-directed medical therapy for heart failure, which included bisoprolol, sacubitril/valsartan, and dapagliflozin. Notably, mineralocorticoid receptor antagonists were not prescribed because she had a history of severe spironolactone-induced rash. Under the aforementioned regimen, her symptoms improved modestly. In December 2024, a cardiac magnetic resonance imaging scan was performed; it revealed myocardial tissue abnormalities and morphological features consistent with LV noncompaction. Late gadolinium enhancement was noted in the mid-wall of the interventricular septum (Figure 1C). Short-axis images revealed prominent trabeculations and deep intertrabecular recesses, predominantly involving the inferolateral wall of the left ventricle (Figure 1D).

Figure 1.

(A) Holter monitoring demonstrated short runs of nonsustained ventricular tachycardia. (B) Echocardiogram showed progressive deterioration of left ventricular (LV) function, with ejection fraction 30-35%. (C) The short-axis cardiac magnetic resonance image demonstrates late gadolinium enhancement (LGE) in the mid-wall of the interventricular septum (white arrow) and (D) LV non-compaction with prominent trabeculations and deep intertrabecular recesses over the inferolateral wall of the LV.

The patient had previously reported a family history of cardiac symptoms affecting multiple relatives. Given the suspicion of an inherited cardiomyopathy, comprehensive genetic testing was conducted. The tests identified a heterozygous nonsense variant in DSP (p.Arg150*). When considered alongside the echocardiographic and cardiac magnetic resonance imaging findings, this result supported a diagnosis of DCM associated with a truncating DSP variant. This variant was classified as pathogenic on the basis of its disruption of DSP function and the patient’s clinical course. After informed consent was obtained, cascade genetic testing was performed on 13 additional family members. The tests identified six carriers of the same DSP variant (Figure 2A). Detailed clinical, electrocardiographic, imaging, and laboratory findings of the screened family members are summarized in Table 1. Four carriers exhibited a mild cardiomyopathic phenotype, characterized by mild LV dilation and slightly reduced systolic function on echocardiography (Figure 2B-E). Holter monitoring in these individuals revealed frequent ventricular ectopy, consistent with the arrhythmic burden observed in the proband. One carrier had unremarkable echocardiographic findings (Figure 2F) and normal Holter monitoring and reported only mild palpitations. None of the affected individuals had cutaneous or hair abnormalities.

Figure 2.

(A) Pedigree depicting the distribution of cardiac symptoms and genetic testing results across generations. Striped symbols indicate individuals with cardiac symptoms. Family members who underwent genetic testing are denoted by a central small circle; individuals with a red-filled circle carry the desmoplakin (DSP) variant p.Arg150*. The proband is indicated by an arrow. (B-E) Panels B-E correspond to individuals III-2, III-5, IV-2, and IV-3, respectively. All of them exhibited mild left ventricular dilation with slightly reduced systolic function on echocardiography. (F) Individual IV-5 had unremarkable findings on echocardiography.

Table 1. Clinical characteristics of DSP variant carriers.

Case	Age	Gender	Symptom	Lowest LVEF (%)	Peak NT-proBNP (pmol/L)	CMR findings (fibrosis, LGE)	Holter findings (NSVT, PVC burden)	Medication
III-2	60	Female	Chest pain	40-45	28.7	-	NSVT (-), 1.47%	bisoprolol, valsartan
III-5	55	Female	Angina	46	34	Fibrosis (+), LGE (+)	NSVT (-), 0.65%	bisoprolol, dapagliflozin, sacubitril/valsartan
III-7*	53	Female	Dyspnea	30-35	69	LGE (+)	NSVT (+), 1.53%	bisoprolol, dapagliflozin, sacubitril/valsartan
IV-2	30	Female	Chest tightness	40-45	61.4	-	NSVT (-), 1.83%	amiodarone, valsartan
IV-3	28	Female	Chest pain	44	23.6	-	NSVT (-), 0.85%	bisoprolol, valsartan
IV-5	29	Male	Mild palpitation	50-55	1.7	-	NSVT (-), 0.00%	-

* Proband.

CMR, cardiac magnetic resonance; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; NSVT, nonsustained ventricular tachycardia; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PVC, premature ventricular contraction.

After 14 months of guideline-directed medical therapy for heart failure, the patient exhibited symptomatic improvement accompanied by objective evidence of recovery. The LV ejection fraction increased from 30%-35% to 38%-44%, and the level of N-terminal pro-B-type natriuretic peptide decreased to a nadir of 30.8 pmol/L.

DISCUSSION

DSP is a crucial desmosomal protein that anchors intermediate filaments in cardiomyocytes, thereby maintaining structural integrity during mechanical stress. Pathogenic DSP variants are a well-established cause of ACM, including arrhythmogenic right ventricular cardiomyopathy (ARVC) and its LV phenotypes.¹ The clinical importance of DSP-related cardiomyopathy lies in its arrhythmogenic potential, given that affected individuals often present with VAs and have an increased risk of sudden cardiac death (SCD). An early report describing four families with DSP variants indicated a high incidence of SCD and frequent LV involvement, indicating that DSP-mediated disease is not confined to the right ventricle.⁴ Homozygous truncating DSP variants cause Carvajal syndrome, a recessive cardiocutaneous disorder characterized by childhood-onset DCM, woolly hair, and palmoplantar keratoderma. These findings highlight the vital role of DSP in maintaining structural integrity in both cardiac and epidermal tissues.⁴

Research has elucidated genotype–phenotype correlations in DSP-related cardiomyopathy.⁴ In particular, truncating DSP variants have been associated with a disease mechanism that is distinct from, and more severe than, that observed with missense variants.⁴ Castelletti et al. reported that patients carrying truncating DSP variants tend to develop earlier LV dysfunction and a left-dominant ACM phenotype, whereas those carrying missense variants more often exhibit features of ARVC.⁵ One of the largest case series reported a substantial arrhythmic burden among carriers of truncating DSP variants, with one-third of them experiencing sustained VAs or sudden cardiac arrest during follow-up.⁶

Clinicians should maintain a high index of suspicion for DSP-related cardiomyopathy in patients presenting with arrhythmias. In a multicenter study involving 800 DSP variant carriers, 32.5% did not meet traditional diagnostic criteria for ARVC or DCM; however, many of these individuals still developed VAs over time.⁷ This finding indicates that pathogenic DSP variants can induce overlapping or atypical phenotypes that initially evade standard diagnostic definitions. Recurrent episodes of acute chest pain accompanied by troponin elevation, which may mimic myocarditis, are increasingly recognized as a characteristic clinical feature of DSP-related cardiomyopathy. The overall arrhythmic risk in DSP-related cardiomyopathy is substantial. In the aforementioned cohort (n = 800), 17.4% of all patients experienced sustained VAs over a mean follow-up period of 3.7 years, despite contemporary clinical management.⁷ Given this malignant arrhythmic propensity, early implementation of implantable cardioverter defibrillators should be considered in high-risk patients with DSP-related cardiomyopathy.⁷ Regarding treatment, conventional heart failure therapies are used to manage systolic dysfunction. DSP-related cardiomyopathy also requires careful family evaluation. Therefore, the patient’s diagnosis has crucial implications for relatives, who should undergo appropriate genetic screening.

Multiple DSP variants have been documented in Western cohorts.^3,7 However, reports from Asian populations remain limited. To date, only a single case report from Taiwan has described DSP-related DCM. In that report, Chang et al. identified a different pathogenic DSP variant (c.6384delG) in a Taiwanese family, in which affected individuals presented with DCM but lacked cutaneous or hair involvement.⁸ To the best of our knowledge, the present case is the first report from Asia describing familial cardiomyopathy associated with the DSP variant p.Arg150*. Notably, the same truncating variant has been reported in an Italian ACM cohort, in which the p.Arg150* variant was identified in patients with DCM.⁹ These findings confirm that truncating DSP variants can lead to DCM and VAs without the extracardiac features observed in recessive DSP-related disorders. In our cases, several carriers showed arrhythmic manifestations. Current literature and the 2023 European Society of Cardiology Guidelines support annual Holter monitoring, with earlier reassessment when clinical status changes.¹⁰ Echocardiography and cardiac magnetic resonance imaging are important in initial cardiomyopathy evaluation, while follow-up imaging is guided by clinical presentation. In DSP variant carriers, late gadolinium enhancement and reduced LV ejection fraction (< 45%) are additional SCD risk markers, and prophylactic implantable cardioverter-defibrillator implantation may be considered in higher-risk patients.¹⁰ Further evidence is needed to guide management of asymptomatic DSP variant carriers. In our cases (Table 1), cardiac magnetic resonance imaging, echocardiography, and Holter monitoring were used in combination for carrier assessment.

Our case expands the geographic representation of DSP-related cardiomyopathy and provides additional evidence supporting DSP p.Arg150* as a pathogenic variant. Moreover, this case highlights the clinical importance of recognizing DSP variants as a cause of "idiopathic" DCM. In patients with unexplained DCM, particularly when accompanied by VAs or a positive family history, genetic evaluation can clarify the underlying etiology, guide clinical management, and inform prognosis. Identification of a DSP variant in our patient’s family enabled appropriate risk stratification and cascade screening of relatives, leading to early detection of cardiomyopathy in variant carriers. Early diagnosis of DSP-related cardiomyopathy in relatives allows for timely initiation of heart failure therapy and consideration of implantable cardioverter defibrillators to prevent SCD, ultimately improving clinical outcomes.

LEARNING POINTS

• Truncating DSP variants often present with left-dominant cardiomyopathy characterized by VAs and early systolic dysfunction.

• Unexplained DCM and VAs should prompt consideration of DSP-related disease, particularly in the presence of a suggestive family history. Early diagnosis facilitates timely initiation of guideline-directed heart failure management, thereby improving clinical outcomes and mitigating SCD risk.

• Early genetic screening and cascade testing can help detect subclinical cardiomyopathy, support risk stratification for arrhythmias, and facilitate timely clinical management.

DECLARATION OF CONFLICT OF INTEREST

The authors declare no conflicts of interest.