{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T11:08:21Z","timestamp":1780916901836,"version":"3.54.1"},"reference-count":55,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,1,27]],"date-time":"2020-01-27T00:00:00Z","timestamp":1580083200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,1,27]],"date-time":"2020-01-27T00:00:00Z","timestamp":1580083200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100011301","name":"Children\u2019s Hospital of Wisconsin Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011301","name":"Children\u2019s Hospital of Wisconsin Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32\u2010GM080202"],"award-info":[{"award-number":["T32\u2010GM080202"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["5T35HL072483\u201032"],"award-info":[{"award-number":["5T35HL072483\u201032"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["5T35HL072483\u201034"],"award-info":[{"award-number":["5T35HL072483\u201034"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008980","name":"Medical College of Wisconsin","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008980","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011301","name":"Children\u2019s Hospital of Wisconsin Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011301","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ebstein's anomaly (EA) is a rare congenital heart disease of the tricuspid valve and right ventricle. Patients with EA often manifest with left ventricular noncompaction (LVNC), a cardiomyopathy. Despite implication of cardiac sarcomere genes in some cases, very little is understood regarding the genetic etiology of EA\/LVNC. Our study describes a multigenerational family with at least 10 of 17 members affected by EA\/LVNC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed echocardiography on all family members and conducted exome sequencing of six individuals. After identifying candidate variants using two different bioinformatic strategies, we confirmed segregation with phenotype using Sanger sequencing. We investigated structural implications of candidate variants using protein prediction models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Exome sequencing analysis of four affected and two unaffected members identified a novel, rare, and damaging coding variant in the Kelch\u2010like family member 26 (\n                      <jats:italic>KLHL26<\/jats:italic>\n                      ) gene located on chromosome 19 at position 237 of the protein (GRCh37). This variant region was confirmed by Sanger sequencing in the remaining family members.\n                      <jats:italic>KLHL26<\/jats:italic>\n                      (c.709C\u00a0&gt;\u00a0T p.R237C) segregates only with EA\/LVNC\u2010affected individuals (FBAT\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a0.05). Investigating structural implications of the candidate variant using protein prediction models suggested that the KLHL26 variant disrupts electrostatic interactions when binding to part of the ubiquitin proteasome, specifically Cullin3 (CUL3), a component of E3 ubiquitin ligase.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      In this familial case of EA\/LVNC, we have identified a candidate gene variant,\n                      <jats:italic>KLHL26<\/jats:italic>\n                      (p.R237C), which may have an important role in ubiquitin\u2010mediated protein degradation during cardiac development.\n                    <\/jats:p>\n                  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