PO-02-126 DEEP PHENOTYPING OF DSP-ENCODED DESMOPLAKIN CARRYING GENOTYPE POSITIVE UKBB SUBJECTS REVEALS ECG CHANGES AS A POSSIBLE EARLY DIAGNOSTIC MARKER OF DISEASE

Abstract

Arrhythmogenic cardiomyopathy (ACM) is defined by fibrofatty replacement of the ventricular myocardium with loss of myocytes that can result in arrhythmias, sudden cardiac death, and heart failure, especially in young patients. DSP-encoded desmoplakin is a structural protein integral to the cardiac desmosome. Pathogenic variants in DSP are implicated with ACM and renders carriers uniquely susceptible to inflammation which can mimic myocarditis. Thus, there is a need to identify diagnostically informative markers which can help identify individuals with pathogenic DSP variants and ACM. The study aims to use the UK Biobank (UKBB) to describe clinical markers associated with individuals who host DSP variants that can help identify individuals with ACM predisposition. UKBB participants who had undergone whole exome sequencing, ECG, and cardiovascular MRI were selected for study. DSP variants were identified by ClinVar, InterVar, and predicted loss of function in silico modeling, and interpreted manually using ACMG criteria. Variants were matched by age and sex with controls that were genotype negative (G-) for diagnostic cardiomyopathy and ion channelopathy variants. Quantitative ECG and MRI analyses were used with ICD codes to deep phenotype participants. In 122 putative pathogenic DSP carriers (55.52 ± 7.66 years), 11 (9.0%) had atrial fibrillation and/or flutter on ECG analysis compared to 18 (4.9%) in 366 G- controls (55.52 ± 7.64 years). ECG analysis identified smaller S-wave peak amplitude in lead III (192.95 ± 298.66 vs. 287.11 ± 359.35; p=0.009), and in lead aVF (121.87 ± 199.19 vs. 169.00 ± 237.67; p=0.049) among DSP G+ vs. G- participants. Further, T-wave inversion in anterolateral leads was seen in 13 (10.7%) vs. 20 (5.5%) and in inferior leads in 20 (16.4%) vs. 37 (10.1%) in DSP G+ vs. G- controls, respectively. Individuals who host putatively pathogenic DSP variants have distinct ECG markers that may suggest early stages of ACM development, and thus may aid in guiding prognostication. Future steps include stratifying risk by pathogenicity of DSP variants by ACMG criteria to ascertain a more concrete association of likely-pathogenic variants in DSP with atrial fibrillation and/or flutter. Ongoing studies also include further characterization of DSP variants with more detailed MRI analyses with RV/LV characteristics.