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Previously, we reported a rare PSEN<\/jats:styled-content>2<\/jats:italic> frameshift variant in an early\u2010onset AD<\/jats:styled-content> case (PSEN<\/jats:styled-content>2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates.<\/jats:p><\/jats:sec>Methods<\/jats:title>We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN<\/jats:styled-content>2 K115Efs*11 variant in two families.<\/jats:p><\/jats:sec>Results<\/jats:title>Neuropathological and clinical evaluation confirmed the AD<\/jats:styled-content> diagnosis in two individuals carrying the PSEN<\/jats:styled-content>2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild\u2010type PSEN<\/jats:styled-content>2<\/jats:italic> transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN<\/jats:styled-content>2 K115Efs*11 fibroblasts secrete less A\u03b2<\/jats:italic>1\u201340<\/jats:sub> compared to controls, indicating abnormal \u03b3<\/jats:italic>\u2010secretase activity. Analysis of PSEN<\/jats:styled-content>2<\/jats:italic> transcript levels in brain tissue revealed alternatively spliced PSEN<\/jats:styled-content>2<\/jats:italic> products in patient brain as well as in sporadic AD<\/jats:styled-content> and age\u2010matched control brain.<\/jats:p><\/jats:sec>Interpretation<\/jats:title>These data suggest that PSEN<\/jats:styled-content>2 K115Efs*11 is a likely pathogenic variant associated with AD<\/jats:styled-content>. We uncovered novel PSEN<\/jats:styled-content>2<\/jats:italic> alternative transcripts in addition to previously reported PSEN<\/jats:styled-content>2<\/jats:italic> splice isoforms associated with sporadic AD<\/jats:styled-content>. In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which PSEN<\/jats:styled-content><\/jats:italic> variants may influence AD<\/jats:styled-content> pathogenesis, highlighting the complexity underlying genetic contribution to disease risk.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.755","type":"journal-article","created":{"date-parts":[[2019,3,11]],"date-time":"2019-03-11T02:16:16Z","timestamp":1552270576000},"page":"762-777","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Alternative splicing in a presenilin 2 variant associated with Alzheimer disease"],"prefix":"10.1002","volume":"6","author":[{"given":"Jacquelyn E.","family":"Braggin","sequence":"first","affiliation":[{"name":"Department of Neurology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie A.","family":"Bucks","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith M.","family":"Course","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Department of Medicine University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole L.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryce","family":"Sopher","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"Osnis","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiel D.","family":"Shuey","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimiko","family":"Domoto\u2010Reilly","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Caso","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chizuru","family":"Kinoshita","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn P.","family":"Scherpelz","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe","family":"Cross","sequence":"additional","affiliation":[{"name":"School of Medicine University of Utah Salt Lake City Utah"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Grabowski","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Washington Seattle Washington"},{"name":"Department of Radiology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyyed H. 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