{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T03:21:40Z","timestamp":1784776900538,"version":"3.55.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the\n              <jats:italic>LMNA<\/jats:italic>\n              c.992G&gt;A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other\n              <jats:italic>LMNA<\/jats:italic>\n              mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic\n              <jats:italic>LMNA<\/jats:italic>\n              mutations. A shared haplotype of 1 Mb around\n              <jats:italic>LMNA<\/jats:italic>\n              suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear\n              <jats:italic>LMNA<\/jats:italic>\n              -associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other\n              <jats:italic>LMNA<\/jats:italic>\n              mutations but with a more benign course.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.116.001631","type":"journal-article","created":{"date-parts":[[2017,8,9]],"date-time":"2017-08-09T00:55:17Z","timestamp":1502240117000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["<i>Lamin A\/C<\/i>\n            -Related Cardiac Disease"],"prefix":"10.1161","volume":"10","author":[{"given":"Edgar T.","family":"Hoorntje","sequence":"first","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilse A.","family":"Bollen","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela Q.","family":"Barge-Schaapveld","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence H.","family":"van Tienen","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard J.","family":"te Meerman","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joeri A.","family":"Jansweijer","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthonie J.","family":"van Essen","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul G.","family":"Volders","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina A.","family":"Constantinescu","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"van den Akker","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin Y.","family":"van Spaendonck-Zwarts","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rogier A.","family":"Oldenburg","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo L.","family":"Marcelis","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper J.","family":"van der Smagt","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Hennekam","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aryan","family":"Vink","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Bootsma","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmelien","family":"Aten","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur A.","family":"Wilde","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"van den Wijngaard","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos L.","family":"Broers","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan D.","family":"Jongbloed","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanda","family":"van der Velden","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten P.","family":"van den Berg","sequence":"additional","affiliation":[{"name":"For the author affiliations, please see the Appendix."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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