{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T08:23:01Z","timestamp":1793780581082,"version":"4.6.1"},"reference-count":53,"publisher":"BMJ","issue":"6","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2016,12,19]]},"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymous <jats:italic>KCNQ1<\/jats:italic> p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, in <jats:italic>KCNQ1<\/jats:italic>-encoded Kv7.1.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (<jats:italic>KCNH2-<\/jats:italic>p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overall <jats:italic>KCNQ1<\/jats:italic> transcript levels to assess the effect on splicing.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064)\u2005ms and 14.0 (p=0.014)\u2005ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6\u2005ms, p=0.003) resulting in a QTc of \u223c500\u2005ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in \u223c25% mutant transcripts of the total <jats:italic>KCNQ1<\/jats:italic> transcript levels.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our results provide the first evidence that synonymous variants outside the canonical splice sites in <jats:italic>KCNQ1<\/jats:italic> can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2016-104153","type":"journal-article","created":{"date-parts":[[2017,3,6]],"date-time":"2017-03-06T20:10:23Z","timestamp":1488831023000},"page":"390-398","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1"],"prefix":"10.1136","volume":"54","author":[{"given":"Jamie D","family":"Kapplinger","sequence":"first","affiliation":[{"name":"Mayo Medical School, Mayo Clinic, Rochester, Minnesota, USA"},{"name":"Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, 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Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles R","family":"Kerr","sequence":"additional","affiliation":[{"name":"Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Morrison","sequence":"additional","affiliation":[{"name":"Gitxsan Health Society, Hazelton, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Western Ontario, London, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubhayan","family":"Sanatani","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Arbour","sequence":"additional","affiliation":[{"name":"Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada"},{"name":"Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Mayo Medical School, Mayo Clinic, Rochester, Minnesota, USA"},{"name":"Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, USA"},{"name":"Division of Heart Rhythm Services, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA"},{"name":"Division of Pediatric Cardiology, Department of Pediatrics, Mayo Clinic, Rochester, Minnesota, 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