SPC365

A novel LMNA A/C Truncating variant associates with high-risk cardiomyopathy

Session: SESSÃO DE CASOS CLÍNICOS DE MIOCARDIOPATIAS, VALVULOPATIAS, DOENÇAS DO PERICÁRDIO, CARDIOPATIAS CONGÉNITAS
Speaker: Rita Almeida Carvalho

Congress: CPC 2025
Topic: F. Valvular, Myocardial, Pericardial, Pulmonary, Congenital Heart Disease
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Session Type: Sessão de Casos Clínicos
FP Number: ---
Authors: Rita Almeida Carvalho; Rita Amador; Diogo Fernandes da Rocha; Sérgio Maltês; Christopher Strong; Bruno ML Rocha; Carlos Aguiar

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Aptos,sans-serif"><strong><span style="font-size:12.0pt">Case Report:</span></strong></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:12.0pt">A 44-year-old asymptomatic woman with an extensive family history of heart disease was evaluated at our specialized cardiomyopathy clinic. She had a history of paroxysmal atrial fibrillation (AF), first diagnosed 10 years prior. Her family history was notable for multiple relatives with dilated cardiomyopathy, with onset typically between the ages of 30 and 35. Several relatives had intracardiac electronic devices and/or had undergone heart transplantation, while others had experienced sudden cardiac death (SCD).</span></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:12.0pt">The patient&#39;s physical examination, electrocardiogram (ECG), and transthoracic echocardiography (TTE) were unremarkable. Cardiac magnetic resonance imaging (CMR) revealed a mildly dilated left ventricle (LV) with preserved ejection fraction (EF) and no late gadolinium enhancement (LGE). A 24-hour Holter monitor documented sinus rhythm with paroxysmal episodes of AF, normal atrioventricular (AV) conduction, and no evidence of tachyarrhythmias. </span></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:12.0pt">Genetic testing performed on the index patient identified a novel heterozygous variant in the <em>LMNA</em> gene: NM_170707.4:c.826C&gt;T p.(Gln276). During a subsequent visit, the patient provided additional family history to complete a comprehensive pedigree, including clinical details of affected relatives who had previously undergone genetic testing (see pedigree in Figure 1).</span></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:12.0pt">The same variant identified in the index patient was also found in family members exhibiting the cardiomyopathy phenotype. This variant has not been reported in the literature nor is it listed in population databases such as gnomAD. Given that this truncating variant is predicted to undergo nonsense-mediated decay (NMD), and its co-segregation with disease in affected relatives, it was classified as pathogenic.</span></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:12.0pt">Further evaluation with a 7-day ECG revealed sustained AF and an episode of non-sustained ventricular tachycardia (NSVT) consisting of 11 complexes. The identification of a non-missense <em>LMNA</em> variant increased her estimated LMNA-VTA score from 7.6% to 13% for the 5-year risk of life-threatening ventricular tachyarrhythmias. Given the significant family history and documented NSVT, a decision was made to proceed with the implantation of a subcutaneous implantable cardioverter-defibrillator (ICD) for primary prevention of SCD.</span></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Aptos,sans-serif"><strong><span style="font-size:12.0pt">Conclusion:</span></strong></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:12.0pt">We report a novel LMNA gene variant in a family with multiple members affected by cardiomyopathy. The identification of this variant is clinically relevant, as demonstrated by the present case, adding arrhythmic risk and supporting ICD implantation as primary prevention for SCD. The arrhythmic profile, including AF and substrate for ventricular tachycardia (VT), occurs in this patient despite preserved EF and absence of LGE, underscoring the complexities of arrhythmic risk stratification associated with this variant.</span></span></span></p>