{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T17:24:34Z","timestamp":1793381074668,"version":"4.5.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Dilated cardiomyopathy (DCM) was considered a monogenetic disease that can be caused by over 60 genes. Evidence suggests that the combination of multiple pathogenic variants leads to greater disease severity and earlier onset. So far, not much is known about the prevalence and disease course of multiple pathogenic variants in patients with DCM. To gain insight into these knowledge gaps, we (1) systematically collected clinical information from a well-characterized DCM cohort and (2) created a mouse model.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Complete cardiac phenotyping and genotyping was performed in 685 patients with consecutive DCM. Compound heterozygous digenic (LMNA [lamin]\/titin deletion A-band) with monogenic (LMNA\/wild-type) and wild-type\/wild-type mice were created and phenotypically followed over time.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>One hundred thirty-one likely pathogenic\/pathogenic (LP\/P) variants in robust DCM-associated genes were found in 685 patients with DCM (19.1%) genotyped for the robust genes. Three of the 131 patients had a second LP\/P variant (2.3%). These 3 patients had a comparable disease onset, disease severity, and clinical course to patients with DCM with one LP\/P. The LMNA\/Titin deletion A-band mice had no functional differences compared with the LMNA\/wild-type mice after 40 weeks of follow-up, although RNA-sequencing suggests increased cardiac stress and sarcomere insufficiency in the LMNA\/Titin deletion A-band mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>In this study population, 2.3% of patients with DCM with one LP\/P also have a second LP\/P in a different gene. Although the second LP\/P does not seem to influence the disease course of DCM in patients and mice, the finding of a second LP\/P can be of importance to their relatives.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.122.003788","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T09:00:43Z","timestamp":1679907643000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Prevalence and Clinical Consequences of Multiple Pathogenic Variants in Dilated Cardiomyopathy"],"prefix":"10.1161","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0965-6359","authenticated-orcid":true,"given":"Sophie L.V.M.","family":"Stroeks","sequence":"first","affiliation":[{"name":"Cardiovascular Research Institute Maastricht (CARIM); S.L.V.M.S., T.H.M.H., A.G.R., M.A.S., E.A.V.J., S.R.B.H., J.A.J.V.), Maastricht University, Maastricht, Netherlands."},{"name":"KU Leuven, Cardiovascular Sciences, Belgium (S.L.V.M.S., E.A.V.J., S.R.B.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9502-6841","authenticated-orcid":true,"given":"Ida G.","family":"Lunde","sequence":"additional","affiliation":[{"name":"Genetics, Harvard Medical School, Boston, MA (I.G.L., H.W., J.G.)."},{"name":"Diagnostics and Technology, Akershus University Hospital, Oslo, Norway (I.G.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debby M.E.I.","family":"Hellebrekers","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Maastricht University Medical Center, the Netherlands (D.M.E.I.H., G.R.F.C., I.P.C.K., E.P.K., A.v.d.W., H.G.B., J.A.J.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2041-7746","authenticated-orcid":true,"given":"Godelieve R.F.","family":"Claes","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Maastricht University Medical Center, the Netherlands (D.M.E.I.H., G.R.F.C., I.P.C.K., E.P.K., A.v.d.W., H.G.B., J.A.J.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0225-6424","authenticated-orcid":true,"given":"Hiroko","family":"Wakimoto","sequence":"additional","affiliation":[{"name":"Genetics, Harvard Medical School, Boston, MA (I.G.L., H.W., J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5969-4690","authenticated-orcid":true,"given":"Joshua","family":"Gorham","sequence":"additional","affiliation":[{"name":"Genetics, Harvard Medical School, Boston, MA (I.G.L., H.W., J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0080-2893","authenticated-orcid":true,"given":"Ingrid P.C.","family":"Krapels","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Maastricht University Medical Center, the Netherlands (D.M.E.I.H., G.R.F.C., I.P.C.K., E.P.K., A.v.d.W., H.G.B., J.A.J.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Els K.","family":"Vanhoutte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"van den Wijngaard","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Maastricht University Medical Center, the Netherlands (D.M.E.I.H., G.R.F.C., I.P.C.K., E.P.K., A.v.d.W., H.G.B., J.A.J.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6222-071X","authenticated-orcid":true,"given":"Michiel T.H.M.","family":"Henkens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9228-8045","authenticated-orcid":true,"given":"Anne G.","family":"Raafs","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute Maastricht (CARIM); S.L.V.M.S., T.H.M.H., A.G.R., M.A.S., E.A.V.J., S.R.B.H., J.A.J.V.), Maastricht University, Maastricht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurits A.","family":"Sikking","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute Maastricht (CARIM); S.L.V.M.S., T.H.M.H., A.G.R., M.A.S., E.A.V.J., S.R.B.H., J.A.J.V.), Maastricht University, Maastricht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos L.V.","family":"Broers","sequence":"additional","affiliation":[{"name":"Genetics and Cell Biology (J.L.V.B., M.N.), Maastricht University, Maastricht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda","family":"Nabben","sequence":"additional","affiliation":[{"name":"Genetics and Cell Biology (J.L.V.B., M.N.), Maastricht University, Maastricht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2006-7064","authenticated-orcid":true,"given":"Elizabeth A.V.","family":"Jones","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute Maastricht (CARIM); S.L.V.M.S., T.H.M.H., A.G.R., M.A.S., E.A.V.J., S.R.B.H., J.A.J.V.), Maastricht University, Maastricht, Netherlands."},{"name":"KU Leuven, Cardiovascular Sciences, Belgium (S.L.V.M.S., E.A.V.J., S.R.B.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9477-7803","authenticated-orcid":true,"given":"Stephane R.B.","family":"Heymans","sequence":"additional","affiliation":[{"name":"KU Leuven, Cardiovascular Sciences, Belgium (S.L.V.M.S., E.A.V.J., S.R.B.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9274-8865","authenticated-orcid":true,"given":"Han G.","family":"Brunner","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Maastricht University Medical Center, the Netherlands (D.M.E.I.H., G.R.F.C., I.P.C.K., E.P.K., A.v.d.W., H.G.B., J.A.J.V.)."},{"name":"Radboud University Medical Center, Human Genetics, Nijmegen, the Netherlands (H.G.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5549-1298","authenticated-orcid":true,"given":"Job A.J.","family":"Verdonschot","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute Maastricht (CARIM); S.L.V.M.S., T.H.M.H., A.G.R., M.A.S., E.A.V.J., S.R.B.H., J.A.J.V.), Maastricht University, Maastricht, Netherlands."},{"name":"Clinical Genetics, Maastricht University Medical Center, the Netherlands (D.M.E.I.H., G.R.F.C., I.P.C.K., E.P.K., A.v.d.W., H.G.B., J.A.J.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2013.105"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-017-0410-8"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab286"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehu301"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/openhrt-2018-000929"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/circgen.120.003031"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1047951118001403"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/561819"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2017.06.008"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jelectrocard.2018.12.015"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2013.16"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/ehf2.13833"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-018-0294-0"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.404541"},{"key":"e_1_3_3_16_2","first-page":"1058","article-title":"Connexin 43 remodeling induced by LMNA gene mutation Glu82Lys in familial dilated cardiomyopathy with atrial ventricular block.","volume":"123","author":"Sun LP","year":"2010","unstructured":"Sun, LP, Wang, L, Wang, H, Zhang, YH, Pu, JL. Connexin 43 remodeling induced by LMNA gene mutation Glu82Lys in familial dilated cardiomyopathy with atrial ventricular block. Chin Med J (Engl). 2010;123:1058\u20131062.","journal-title":"Chin Med J (Engl)"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29042"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.22403"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.3390\/medicina55010017"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.755777"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.117.001749"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10050921"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2018.03.462"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.037934"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2021.5890"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01255-1"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.119.002480"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv522"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1227764"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3010134"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI19448"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.147.5.913"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI70108"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2484"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471142727.mb0412s94"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1516767"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38639"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0145284"}],"container-title":["Circulation: Genomic and Precision Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCGEN.122.003788","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T01:31:49Z","timestamp":1715563909000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCGEN.122.003788"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4]]},"references-count":37,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,4]]}},"alternative-id":["10.1161\/CIRCGEN.122.003788"],"URL":"https:\/\/doi.org\/10.1161\/circgen.122.003788","relation":{},"ISSN":["2574-8300"],"issn-type":[{"value":"2574-8300","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4]]},"assertion":[{"value":"2022-03-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}