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Med."],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Here we report an infant with clinical findings suggestive of Jervell and Lange-Nielsen syndrome (JLNS), including a prolonged QT interval (LQTS) and chronic bilateral sensorineural deafness. NGS analysis revealed one known heterozygous pathogenic missense variant, KCNQ1 p.R259L, previously associated with LQTS but insufficient to explain the cardioauditory disorder. In a screening of proximal intronic regions, we found a heterozygous variant, <jats:italic>KCNQ1<\/jats:italic> c.1686\u22129\u2009T\u2009&gt;\u2009C, absent from controls and previously undescribed. Several splicing prediction tools returned low scores for this intronic variant. Driven by the proband\u2019s phenotype rather than the neutral predictions, we have characterized this rare intronic variant. Family analysis has shown that the proband inherited the missense and the intronic variants from his mother and father, respectively. A minigene splicing assay revealed that the intronic variant induced an additional transcript, arising from skipping of exon 14, which was translated into a truncated protein in transfected cells. The splice-out of exon 14 creates a frameshift in exon 15 and a stop codon in exon 16, which is the last exon of <jats:italic>KCNQ1<\/jats:italic>. This mis-spliced transcript is expected to escape nonsense-mediated decay and predicted to encode a truncated loss-of-function protein, KCNQ1 p.L563Kfs*73. The analysis of endogenous <jats:italic>KCNQ1<\/jats:italic> expression in the blood of the proband\u2019s parents detected the aberrant transcript only in the patient\u2019s father. Taken together, these analyses confirmed the proband\u2019s diagnosis of JLNS1 and indicated that c.1686\u22129\u2009T\u2009&gt;\u2009C is a cryptic splice-altering variant, expanding the known genetic spectrum of biallelic <jats:italic>KCNQ1<\/jats:italic> variant combinations leading to JLNS1.<\/jats:p>","DOI":"10.1038\/s41525-021-00183-y","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T11:03:59Z","timestamp":1614855839000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A cryptic splice-altering KCNQ1 variant in trans with R259L leading to Jervell and Lange-Nielsen syndrome"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9762-7018","authenticated-orcid":false,"given":"Mario","family":"Torrado","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Germ\u00e1n","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5891-5372","authenticated-orcid":false,"given":"Christian A.","family":"Ganoza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7671-2405","authenticated-orcid":false,"given":"Emilia","family":"Maneiro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego","family":"Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7766-1251","authenticated-orcid":false,"given":"Natalia","family":"Sonicheva-Paterson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isaac","family":"Rosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Pablo","family":"Ochoa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"Santom\u00e9","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Vasichkina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Monserrat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"183_CR1","doi-asserted-by":"crossref","unstructured":"Amin, A. 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G.F., C.G., E.M., D.G., N.S., I.R., J.P.O., and L.S. were or are employees of Health in Code during the course of this project. The other authors report no conflicts.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"21"}}