SPC365

Co-segregation analysis of a novel FLNC variant in a family with ALVC and malignant arrhythmic risk

Session: Prémio Melhor Caso Clínico
Speaker: Márcia Presume

Congress: CPC 2026
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Session Type: Sessão de Prémios
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Authors: Márcia Presume; Débora Correia; Rita Almeida Carvalho; Rita Amador; Sérgio Maltês; Sara Guerreiro; Oana Moldovan; Sara Querido; Carlos Aguiar; Marisa Trabulo; Bruno Rocha
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:&quot;Times New Roman&quot;,&quot;serif&quot;"><strong><span style="font-size:11.0pt"><span style="font-family:&quot;Arial&quot;,&quot;sans-serif&quot;"><span style="color:black">Introduction:&nbsp;</span></span></span></strong></span></span><span style="font-size:12pt"><span style="font-family:&quot;Times New Roman&quot;,&quot;serif&quot;"><span style="font-size:11.0pt"><span style="font-family:&quot;Arial&quot;,&quot;sans-serif&quot;"><span style="color:black">Filamin C (FLNC)-related arrhythmogenic left ventricular cardiomyopathy (ALVC) is a left ventricular (LV)-dominant cardiac disease characterized by myocardial fibrosis, high arrhythmic risk and sudden cardiac death (SCD). We report a family in whom genotype&ndash;phenotype co-segregation supports reclassification of a previously variant of uncertain significance (VUS) to likely pathogenic - the first description for this mutation.</span></span></span></span></span></p>

<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:&quot;Times New Roman&quot;,&quot;serif&quot;"><strong><span style="font-size:11.0pt"><span style="font-family:&quot;Arial&quot;,&quot;sans-serif&quot;"><span style="color:black">Case:&nbsp;</span></span></span></strong><span style="font-size:11.0pt"><span style="font-family:&quot;Arial&quot;,&quot;sans-serif&quot;"><span style="color:black">A 43-year-old male with a history of IgA nephropathy was referred to Cardiology for pre-kidney transplant (KT) evaluation. Family history included non-ischemic dilated cardiomyopathy (mother, death at 58 years) and SCD (maternal uncle, at 50 years). He was asymptomatic. Transthoracic echocardiogram (TTE) showed a severely dilated LV, mildly reduced LV&nbsp;ejection fraction (LVEF 45%)</span></span></span> <span style="font-size:11.0pt"><span style="font-family:&quot;Arial&quot;,&quot;sans-serif&quot;"><span style="color:black">and infero-posterior wall motion abnormalities. Coronary angiography was normal. In 2017, a cardiac magnetic resonance (CMR) with contrast was not performed given a possible risk for nephrogenic systemic fibrosis, and a diagnosis of embolic myocardial infarction (or myocarditis) was presumed. </span></span></span></span></span><span style="font-size:11.0pt"><span style="font-family:&quot;Arial&quot;,&quot;sans-serif&quot;"><span style="color:black">He was cleared and received a living-donor KT from his sister.</span></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,&quot;sans-serif&quot;"><span style="font-family:&quot;Arial&quot;,&quot;sans-serif&quot;"><span style="color:black">At 49-years of age, he remained asymptomatic with preserved KT function.</span></span> <span style="font-family:&quot;Arial&quot;,&quot;sans-serif&quot;"><span style="color:black">Given persistent suspicion for a familial cardiomyopathy, further workup was performed. CMR demonstrated reduced LVEF (43%) and extensive &ldquo;ring-like&rdquo; mid-myocardial and sub-epicardial late gadolinium enhancement (LGE), consistent with ALVC. Genetic testing identified a heterozygous FLNC c.2929+5G&gt;A variant, initially classified as a variant of uncertain significance (hot-VUS). In this context, a primary-prevention implantable cardioverter-defibrillator (ICD) was implanted and physical-activity moderation was advised.</span></span></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,&quot;sans-serif&quot;"><span style="font-family:&quot;Arial&quot;,&quot;sans-serif&quot;"><span style="color:black">First-degree relatives were referred for screening, with the son and sister not exhibiting the phenotype. </span></span><span style="font-family:&quot;Arial&quot;,&quot;sans-serif&quot;">However, extended family assessment revealed a first cousin with an established cardiomyopathy characterised by moderate LV dysfunction. Genetic testing confirmed that she carried the same FLNC variant. Cascade screening within this branch identified two additional genotype-phenotype positive relatives: the cousin&rsquo;s sister and daughter. Although asymptomatic, the cousin had moderate LV systolic impairment on screening TTE and CMR confirming a &ldquo;ring-like&rdquo; fibrosis pattern fulfilling Padua criteria. ICD implantation in primary prevention was undertaken in the cousin&rsquo;s sister based on genetic diagnosis, LV dysfunction and extensive LGE. The cousin&rsquo;s daughter had similar LGE findings although LVEF is preserved and currently awaiting<span style="color:black"> electrophysiological risk stratification.</span></span></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,&quot;sans-serif&quot;"><strong><span style="font-family:&quot;Arial&quot;,&quot;sans-serif&quot;"><span style="color:black">Conclusions:&nbsp;</span></span></strong></span></span><span style="font-size:11pt"><span style="font-family:Calibri,&quot;sans-serif&quot;"><span style="font-family:&quot;Arial&quot;,&quot;sans-serif&quot;"><span style="color:black">Genotype&ndash;phenotype co-segregation in this family supports reclassification of this FLNC VUS to likely pathogenic, with direct implications for ICD decision-making and cascade screening.</span></span></span></span></p>