{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T22:17:16Z","timestamp":1794521836144,"version":"4.9.1"},"reference-count":24,"publisher":"American Medical Association (AMA)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2025,9,1]]},"abstract":"<jats:sec id=\"ab-hoi250033-4\">\n                    <jats:title>Importance<\/jats:title>\n                    <jats:p>\n                      Prior studies have suggested that patients with nonmissense (ie, truncating) variants causing\n                      <jats:italic>LMNA<\/jats:italic>\n                      cardiomyopathy have worse arrhythmic outcomes compared to those with missense variants. However, the effect of the spatial distribution of missense and truncating variants on clinical outcomes remains poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-hoi250033-5\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To determine the association of the spatial distribution of missense and truncating\n                      <jats:italic>LMNA<\/jats:italic>\n                      variants with cardiac outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-hoi250033-6\">\n                    <jats:title>Design, Setting, and Participants<\/jats:title>\n                    <jats:p>\n                      This multicenter, retrospective, observational cohort study used data from an international registry (from January 2013 on) and data derived from tertiary cardiomyopathy centers (January 2000 and June 2017). Patients with likely pathogenic\/pathogenic\n                      <jats:italic>LMNA<\/jats:italic>\n                      variants and no prior malignant ventricular arrhythmia (VA) were eligible for inclusion. Data analysis was completed from March 2022 to March 2025.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-hoi250033-7\">\n                    <jats:title>Main Outcomes and Measures<\/jats:title>\n                    <jats:p>\n                      The primary outcome of time to VA was defined as sudden cardiac death, appropriate implantable cardioverter-defibrillator therapy, or other manifestations of hemodynamically unstable VA. The secondary composite outcome of advanced heart failure was defined as nonsudden cardiac death, implantation of a left ventricular assist device, or cardiac transplant. Outcomes were stratified by type of variant (missense or truncating), affected transcript position (head, rod, or tail), and location on the\n                      <jats:italic>LMNA<\/jats:italic>\n                      gene.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-hoi250033-8\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 718 patients were included, among whom mean (SD) age was 41.1 (14.3) years, 381 patients (53.1%) were female, and mean (SD) baseline left ventricular ejection fraction was 55.8% (13.3%). Over a median follow-up of 4.2 years, 223 patients experienced the primary outcome of malignant VA and 109 experienced the secondary outcome of advanced heart failure. Patients with truncating variants had a higher risk of VA (hazard ratio [HR], 1.72; 95% CI, 1.19-2.48;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u2009.004) but no difference in advanced heart failure (HR, 0.94; 95% CI, 0.64-1.40;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u2009.77) compared with patients with missense variants. There were no significant differences in the primary and secondary outcomes when stratifying truncating variants by location on the\n                      <jats:italic>LMNA<\/jats:italic>\n                      gene or transcript position. In contrast, on multivariable analysis, missense variants affecting the tail domain of\n                      <jats:italic>LMNA<\/jats:italic>\n                      (HR, 0.35; 95% CI, 0.16-0.78;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u2009.02) and located in exons 7 through 12 (HR, 0.39; 95% CI, 0.17-0.89;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u2009.035) were associated with a significantly lower risk of the primary outcome of malignant VA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-hoi250033-9\">\n                    <jats:title>Conclusions and Relevance<\/jats:title>\n                    <jats:p>In this retrospective cohort study, truncating LMNA variants were associated with worse arrhythmic outcomes independent of variant position, whereas missense variants affecting the tail domain and located in exons 7 through 12 had better arrhythmic and heart failure outcomes. Understanding the mechanisms underlying these differences may have future therapeutic implications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1001\/jamacardio.2025.2069","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T11:00:38Z","timestamp":1751454038000},"page":"896","source":"Crossref","is-referenced-by-count":25,"title":["Location of\n                    <i>LMNA<\/i>\n                    Variants and Clinical Outcomes in Cardiomyopathy"],"prefix":"10.1001","volume":"10","author":[{"given":"Ashwin","family":"Bhaskaran","sequence":"first","affiliation":[{"name":"Department of Cardiology, Westmead Hospital, Sydney, New South Wales, Australia"},{"name":"Westmead Applied Research Centre, University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabah","family":"Ben Yaou","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence Maladies Neuromusculaires Nord\/Est\/Ile-de-France, FILNEMUS, Institut de Myologie, Assistance Publique\u2013H\u00f4pitaux de Paris (AP-HP), Paris, France."},{"name":"Institut de Myologie, Centre de Recherche en Myologie, Sorbonne Universit\u00e9, INSERM, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam S.","family":"Helms","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, University of Michigan, Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdallah","family":"Fayssoil","sequence":"additional","affiliation":[{"name":"Cardiology Department, Raymond Poincar\u00e9 Hospital, AP-HP, Garches, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Richard","sequence":"additional","affiliation":[{"name":"DMU BioGemH, Functional Unit of Molecular and Cellular Cardiogenetics and Myogenetics, Centre de G\u00e9n\u00e9tique Mol\u00e9culaire et Chromosomique, GH Piti\u00e9 Salp\u00eatri\u00e8re, AP-HP, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Stojkovic","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence Maladies Neuromusculaires Nord\/Est\/Ile-de-France, FILNEMUS, Institut de Myologie, Assistance Publique\u2013H\u00f4pitaux de Paris (AP-HP), Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Anselme","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Normandie Univ, UNIROUEN, U1096, CHU Rouen, Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Labombarda","sequence":"additional","affiliation":[{"name":"Cardiology Department, University Hospital of Caen, UR 4650 Unicaen, Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Chikhaoui","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence Maladies Neuromusculaires 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G\u00e9nomique des Maladies de Syst\u00e8me et d\u2019Organe, H\u00f4pital Cochin, Centre\u2013Universit\u00e9 Paris Cit\u00e9, AP-HP, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Vigouroux","sequence":"additional","affiliation":[{"name":"National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity, Department of Endocrinology, Diabetology and Reproductive Endocrinology, Saint-Antoine University Hospital, AP-HP, Paris, France"},{"name":"Saint-Antoine Research Centre, Institute of Cardiometabolism and Nutrition, Sorbonne University, Inserm U938, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Dembele","sequence":"additional","affiliation":[{"name":"AFM Telethon, Evry, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perry","family":"Elliott","sequence":"additional","affiliation":[{"name":"Inherited Cardiovascular Diseases Unit, University College London and St Bartholomew\u2019s Hospital, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Savvatis","sequence":"additional","affiliation":[{"name":"Inherited Cardiovascular Diseases Unit, University College London and St Bartholomew\u2019s Hospital, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Zeppenfeld","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassina","family":"Bouguerra","sequence":"additional","affiliation":[{"name":"Cardiology Department, FILNEMUS, Centre de R\u00e9f\u00e9rence des Maladies, Neuromusculaires Nord\/Est\/Ile de France, Cochin Hospital, AP-HP, Paris Cit\u00e9 Universit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Charron","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Maladies Cardiaques H\u00e9r\u00e9ditaires ou Rares, Department of Genetics, INSERM UMRS 1166, Institute of Cardiometabolism and Nutrition, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Sorbonne University, AP-HP, Paris, France"},{"name":"Department of Cardiology, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, AP-HP, Paris, France"},{"name":"ACTION Study Group, H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Westmead Hospital, Sydney, New South Wales, Australia"},{"name":"Westmead Applied Research Centre, University of Sydney, Sydney, New South Wales, 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