{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T07:03:14Z","timestamp":1775113394998,"version":"3.50.1"},"reference-count":20,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007627","name":"Common Fund for Commodities","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007627","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alternative use of short distance tandem sites such as NAGN<jats:sub>n<\/jats:sub>AG are a common mechanism of alternative splicing; however, single nucleotide variants are rarely reported as likely to generate or to disrupt tandem splice sites. We identify a pathogenic intron 5 S<jats:italic>TK11<\/jats:italic> variant (NM_000455.4:c.[735\u20106A&gt;G];[=]) segregating with the mucocutaneous features but not the hamartomatous polyps of Peutz\u2013Jeghers syndrome in two individuals. By RNAseq analysis of peripheral blood mRNA, this variant was shown to generate a novel and preferentially used tandem proximal splice acceptor (A<jats:styled-content><jats:bold>AG<\/jats:bold><\/jats:styled-content>TGA<jats:styled-content><jats:bold>AG<\/jats:bold><\/jats:styled-content>). The variant transcript (NM_000455.4:c.734_734\u2009+\u20091insTGAAG), which encodes a frameshift (p.[Tyr246Glufs*43]) constituted 36%\u201343% of <jats:italic>STK11<\/jats:italic> transcripts suggesting partial escape from nonsense mediated mRNA decay and translation of a truncated protein. A review of the ClinVar database identified other similar variants. We suggest that nucleotide changes creating or disrupting tandem alternative splice sites are a pertinent disease mechanism and require contextualization for clinical reporting. Additionally, we hypothesize that some pathogenic <jats:italic>STK11<\/jats:italic> variants cause an attenuated phenotype.<\/jats:p>","DOI":"10.1002\/ajmg.a.62942","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T08:24:16Z","timestamp":1660119856000},"page":"3089-3095","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Can tandem alternative splicing and evasion of premature termination codon surveillance contribute to attenuated <scp>Peutz\u2013Jeghers<\/scp> syndrome?"],"prefix":"10.1002","volume":"188","author":[{"given":"Nour","family":"Gazzaz","sequence":"first","affiliation":[{"name":"Department of Medical Genetics and Provincial Medical Genetics Program University of British Columbia and Women's Hospital of British Columbia  Vancouver British Columbia Canada"},{"name":"Department of Pediatrics King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F. Graeme","family":"Frost","sequence":"additional","affiliation":[{"name":"National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Alderman","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Provincial Medical Genetics Program University of British Columbia and Women's Hospital of British Columbia  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phillip A.","family":"Richmond","sequence":"additional","affiliation":[{"name":"The Rare Disease Discovery Hub BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua","family":"Dalmann","sequence":"additional","affiliation":[{"name":"The Rare Disease Discovery Hub BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Lin","sequence":"additional","affiliation":[{"name":"The Rare Disease Discovery Hub BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Areesha","family":"Salman","sequence":"additional","affiliation":[{"name":"The Rare Disease Discovery Hub BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate L.","family":"Del Bel","sequence":"additional","affiliation":[{"name":"The Rare Disease Discovery Hub BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Lehman","sequence":"additional","affiliation":[{"name":"The Rare Disease Discovery Hub BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart E.","family":"Turvey","sequence":"additional","affiliation":[{"name":"The Rare Disease Discovery Hub BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3097-241X","authenticated-orcid":false,"given":"Cornelius F.","family":"Boerkoel","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Provincial Medical Genetics Program University of British Columbia and Women's Hospital of British Columbia  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Praveen F.","family":"Cherukuri","sequence":"additional","affiliation":[{"name":"Imagenetics, Sanford Health and Research Center and Sanford School of Medicine University of South Dakota  Sioux Falls South Dakota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.1211"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20253"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.27"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2020.05.030"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1469"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj20080557"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-021-03943-2"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.13900"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkl924"},{"key":"e_1_2_10_12_1","volume-title":"GeneReviews([R])","author":"McGarrity T. 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