{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T10:48:20Z","timestamp":1782470900164,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,24]]},"group-title":"Cardiovascular Medicine","reference-count":37,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH NHLBI","award":["R01HL153447"],"award-info":[{"award-number":["R01HL153447"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Cardiomyopathy and channelopathy (CC) gene variants have been linked to sudden cardiac arrest (SCA) or death (SCD) in small, selected pedigree or post-mortem studies of arrhythmic mitral valve prolapse (MVP). However, the utility of clinical whole exome sequencing (WES) panels as a risk stratification tool in unselected MVP samples is unknown.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>The goal of the study was to test the utility of clinical WES panels with CC variant screening for arrhythmic risk stratification in MVP.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed research-based WES in 203 consecutive MVPs without other arrhythmic substrate. Variants were filtered for rare (&lt;0.1%) and protein altering variants in 157 CC genes within an existing clinical panel and annotated with a clinical significance predictor. Overall frequency of CC variants was compared to a sample of general population exomes from gnomad v4.1.0. We assessed a composite severe arrhythmic outcome of SCD or frequent ectopy\/ventricular tachycardia or ventricular fibrillation\/SCA requiring catheter ablation or defibrillator implantation, respectively.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>CC variants were more common in MVPs compared to the general population (RR: 4.3, p &lt; 0.01). Pathogenic\/Likely Pathogenic (P\/LP) variants were identified in 18 MVPs (9%; 8 CC variants among 12 genes). P\/LP variants were independently associated with the composite arrhythmic outcome after adjustment for traditional imaging parameters of risk including mitral annular disjunction and bileaflet involvement (OR: 1.23 [95% CI: 1.03 \u2013 1.47], p = 0.01). P\/LP variant carriers were at greater arrhythmic risk in time-to-event analyses starting at birth (HR: 2.87 [95% CI: 1.24 \u2013 6.62], p = 0.01).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>A subset of MVPs with P\/LP variants in CC genes are at higher arrhythmic risk. A clinical WES panel inclusive of CC variants may represent a valuable arrhythmic risk stratification tool in MVP beyond traditional imaging parameters.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Clinical Perspective<\/jats:title>\n                  <jats:sec>\n                    <jats:title>What Is Known<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Cardiomyopathy\/channelopathy gene variants have been linked to sudden cardiac arrest or death in small, selected pedigree or post-mortem studies of arrhythmic mitral valve prolapse (MVP).<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Imaging studies have highlighted a diffuse myopathic process in patients with arrhythmic MVP and their family members.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>What The Study Adds<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>In consecutive MVP patients, cardiomyopathy\/channelopathy genetic mutations are linked to a subclinical myopathy by strain echocardiography and a greater risk for severe ventricular arrhythmias independently of bileaflet involvement and mitral annular disjunction<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>A clinical whole exome sequencing panel inclusive of cardiomyopathy\/channelopathy genetic variants may represent a valuable arrhythmic risk stratification tool in MVP beyond traditional imaging parameters<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Abstract Figure<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:label>Graphical Abstract:<\/jats:label>\n                    <jats:caption>\n                      <jats:title>Cardiomyopathy\/Channelopathy Genetic Testing in Mitral Valve Prolapse.<\/jats:title>\n                      <jats:p>Genetic samples from 203 MVPs were sequenced, and MVPs were subsequently divided based on whether they carried P\/LP variants in CC genes (Top Left) or not. P\/LP variants were identified in multiple genes associated with a variety of CC conditions (Bottom Left). A Kaplan-Meier curve demonstrates that P\/LP variant carriers are at higher risk for the composite arrhythmic outcome beginning at birth (Right).<\/jats:p>\n                    <\/jats:caption>\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"26356215v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.22.26356215","type":"posted-content","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T18:30:10Z","timestamp":1782325810000},"source":"Crossref","is-referenced-by-count":0,"title":["Utility of genetic screening for the prediction of severe arrhythmic outcomes in mitral valve prolapse"],"prefix":"10.64898","author":[{"given":"Rohit","family":"Jhawar","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of California San Francisco, San Francisco, CA, 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