{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T10:40:41Z","timestamp":1788777641832,"version":"build-2803163510"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Heterozygous\n              <jats:italic>TTN<\/jats:italic>\n              truncating variants cause 10% to 20% of idiopathic dilated cardiomyopathy (DCM). Although variants which disrupt canonical splice signals (ie, invariant dinucleotide of the splice donor site, invariant dinucleotide of the splice acceptor site) at exon-intron junctions are readily recognized as\n              <jats:italic>TTN<\/jats:italic>\n              truncating variants, the effects of other nearby sequence variations on splicing and their contribution to disease is uncertain.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              Rare variants of unknown significance located in the splice regions of highly expressed\n              <jats:italic>TTN<\/jats:italic>\n              exons from 203 DCM cases, 3329 normal subjects, and clinical variant databases were identified. The effects of these variants on splicing were assessed using an in vitro splice assay.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Splice-altering variants of unknown significance were enriched in DCM cases over controls and present in 2% of DCM patients (\n              <jats:italic>P<\/jats:italic>\n              =0.002). Application of this method to clinical variant databases demonstrated 20% of similar variants of unknown significance in\n              <jats:italic>TTN<\/jats:italic>\n              splice regions affect splicing. Noncanonical splice-altering variants were most frequently located at position +5 of the donor site (\n              <jats:italic>P<\/jats:italic>\n              =4.4\u00d710\n              <jats:sup>7<\/jats:sup>\n              ) and position -3 of the acceptor site (\n              <jats:italic>P<\/jats:italic>\n              =0.002). SpliceAI, an emerging in silico prediction tool, had a high positive predictive value (86%\u201395%) but poor sensitivity (15%\u201350%) for the detection of splice-altering variants. Alternate exons spliced out of most\n              <jats:italic>TTN<\/jats:italic>\n              transcripts frequently lacked the consensus base at +5 donor and \u22123 acceptor positions.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Noncanonical splice-altering variants in\n              <jats:italic>TTN<\/jats:italic>\n              explain 1-2% of DCM and offer a 10-20% increase in the diagnostic power of\n              <jats:italic>TTN<\/jats:italic>\n              sequencing in this disease. These data suggest rules that may improve efforts to detect splice-altering variants in other genes and may explain the low percent splicing observed for many alternate\n              <jats:italic>TTN<\/jats:italic>\n              exons.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.121.003389","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T09:01:56Z","timestamp":1630400516000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":27,"title":["Contribution of Noncanonical Splice Variants to\n            <i>TTN<\/i>\n            Truncating Variant Cardiomyopathy"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3561-796X","authenticated-orcid":true,"given":"Parth N.","family":"Patel","sequence":"first","affiliation":[{"name":"Department of Genetics (P.N.P., K.I., J.A.L.W., A.H., M.Y.J., J.M.G., S.R.D., L.L., B.M., C.E.S., J.G.S.), Harvard Medical School, Boston, MA."},{"name":"Department of Medicine, Brigham and Women\u2019s Hospital (P.N.P., A.H., M.Y.J.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1843-773X","authenticated-orcid":true,"given":"Kaoru","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Genetics (P.N.P., K.I., J.A.L.W., A.H., M.Y.J., J.M.G., S.R.D., L.L., B.M., C.E.S., J.G.S.), Harvard Medical School, Boston, MA."},{"name":"Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (K.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3782-4770","authenticated-orcid":true,"given":"Jon A.L.","family":"Willcox","sequence":"additional","affiliation":[{"name":"Department of Genetics (P.N.P., K.I., J.A.L.W., A.H., M.Y.J., J.M.G., S.R.D., L.L., B.M., C.E.S., J.G.S.), Harvard 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