{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T15:51:25Z","timestamp":1789919485224,"version":"4.0.1"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Idiopathic dilated cardiomyopathy (\n              <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n              ) is typically diagnosed in adulthood, yet familial cases exhibit variable age\u2010dependent penetrance and a subset of patients develop sporadic\n              <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n              in childhood. We sought to discover the molecular basis of sporadic\n              <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n              in an 11\u2010year\u2010old female with severe heart failure necessitating cardiac transplantation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Parental echocardiograms excluded asymptomatic\n              <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n              . Whole exome sequencing was performed on the family trio and filtered for rare, deleterious, recessive, and de novo variants. Of the 8 candidate genes identified, only 2 had a role in cardiac physiology. A de novo missense mutation in\n              <jats:italic>\n                <jats:styled-content style=\"fixed-case\">TNNT<\/jats:styled-content>\n                2\n              <\/jats:italic>\n              was identified, previously reported and functionally validated in familial\n              <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n              with markedly variable penetrance. Additionally, recessive compound heterozygous truncating mutations were identified in\n              <jats:italic>\n                <jats:styled-content style=\"fixed-case\">XIRP<\/jats:styled-content>\n                2\n              <\/jats:italic>\n              , a member of the ancient\n              <jats:italic>Xin<\/jats:italic>\n              gene family, which governs intercalated disc (\n              <jats:styled-content style=\"fixed-case\">ICD<\/jats:styled-content>\n              ) maturation. Histomorphological analysis of explanted heart tissue revealed misregistration, mislocalization, and shortening of\n              <jats:styled-content style=\"fixed-case\">ICD<\/jats:styled-content>\n              s, findings similar to\n              <jats:italic>Xirp2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>\u2212\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              The synergistic effects of\n              <jats:italic>\n                <jats:styled-content style=\"fixed-case\">TNNT<\/jats:styled-content>\n                2\n              <\/jats:italic>\n              and\n              <jats:italic>\n                <jats:styled-content style=\"fixed-case\">XIRP<\/jats:styled-content>\n                2\n              <\/jats:italic>\n              mutations, resulting in perturbed sarcomeric force generation and transmission, respectively, would account for an early\u2010onset heart failure phenotype. Whereas the importance of Xin proteins in cardiac development has been well established in animal models, this study implicates\n              <jats:italic>\n                <jats:styled-content style=\"fixed-case\">XIRP<\/jats:styled-content>\n                2\n              <\/jats:italic>\n              as a novel modifier gene in the pathogenesis of\n              <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n              .\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.115.002443","type":"journal-article","created":{"date-parts":[[2015,12,10]],"date-time":"2015-12-10T04:45:35Z","timestamp":1449722735000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Exome Sequencing Identifies Pathogenic and Modifier Mutations in a Child With Sporadic Dilated Cardiomyopathy"],"prefix":"10.1161","volume":"4","author":[{"given":"Pamela A.","family":"Long","sequence":"first","affiliation":[{"name":"Mayo Graduate School Molecular Pharmacology and Experimental Therapeutics Track Mayo Clinic Rochester MN"},{"name":"Cardiovascular Genetics Research Laboratory Mayo Clinic Rochester MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon T.","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Arizona Medical Center Tucson AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared M.","family":"Evans","sequence":"additional","affiliation":[{"name":"Division of Biomedical Statistics and Informatics Department of Health Sciences Research Mayo Clinic Rochester MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Olson","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Research Laboratory Mayo Clinic Rochester MN"},{"name":"Division of Pediatric Cardiology Department of Pediatric and Adolescent Medicine Mayo Clinic Rochester MN"},{"name":"Division of Cardiovascular Diseases Department of Internal Medicine Mayo Clinic Rochester MN"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2013.08.005"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2013.08.006"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199201093260201"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(97)00433-6"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(97)00434-8"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2013.105"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62862"},{"key":"e_1_3_2_9_2","first-page":"1235","volume-title":"Moss and Adams' Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adult","author":"Olson TM","year":"2013","unstructured":"Olson TM, Chan DP. 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