PO64 Sudden Death: 10-Year Search for the Underlying Cause

Abstract 24-year-old man, referred in 2012 to a cardiology consultation in Zurich after his mother’s sudden death at the age of 49, who’s post-mortem anatomopathological examination revealed fibro-fatty tissue in both ventricles, with diffuse involvement of the left ventricle (LV). The post-mortem genetic study identified a variant in the PKP2 gene (c.2392A>G, p.T798A), classified as pathogenic based on in silico methods, and a variant in the DSG2 gene (c.877A>G, p.I293V) of uncertain significance. Sudden death was attributed to arrhythmogenic cardiomyopathy (ACM) with predominant LV involvement. The patient’s ECG showed no significant alterations, but cardiac magnetic resonance imaging (CMR) revealed LV dysfunction (ejection fraction [EF] 48%), with global hypokinesia and mid-myocardial and subepicardial late gadolinium enhancement in the inferior, anterolateral, and anteroseptal regions, without right ventricular (RV) involvement. The 24-hour Holter monitoring showed >1000 multifocal ventricular extrasystoles. Right-sided interventricular septal endomyocardial biopsy showed no abnormalities. The genetic study revealed the same variants identified in his mother. Based on these findings and a history of syncope, a primary-prevention implantable cardioverter-defibrillator (ICD) was implanted. The clinical case of this patient was published in Circulation in 2015, describing a new PKP2 variant associated with LV ACM. In 2022, the patient returned to Portugal and was referred to our center. A new CMR (Image 1) showed a non-dilated LV with EF of 38% due to global hypokinesia; non-dilated RV with EF of 36%; and extensive subepicardial late gadolinium enhancement in the LV free wall and mid-myocardial enhancement in the inferior septum, involving almost all LV walls circumferentially (a “ring-like” pattern). Medical therapy was adjusted, and a subsequent echocardiogram showed normalization of LV (EF 56%) and RV function. No arrhythmic events were recorded. A new genetic study revealed a likely pathogenic variant of the DSP gene [deletion c.1420-226_2130+392del p.(Lys474_Lys710del)], resulting in deletion of 237 amino acids, encompassing exons 12 to 15 of the gene, considered critical functional domains. The PKP2 gene variant is currently classified as a variant of uncertain significance. Thus, the diagnosis was established as non-dilated cardiomyopathy with biventricular involvement secondary to a DSP gene variant. This case illustrates the importance of rigor in interpreting genetic results and critical integration with clinical data, both in clinical practice and in the review of published cases. PKP2 gene variants are associated with RV ACM, while DSP gene variants often present with predominant LV disease and a “ring-like” late enhancement pattern. In silico methods, although useful, are insufficient to classify a new variant as pathogenic. Without access to the Swiss genetic study report, it is possible that the DSP gene was not analyzed post-mortem or that this deletion was not detected by PCR-based methods. Repeating the genetic study had a clear impact not only on the patient’s diagnosis but also on family screening, preventing relatives from being incorrectly classified and managed. This case highlights the importance of these patients being followed in specialized cardiomyopathy centers.