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Many mutations in the amyloid precursor protein (<jats:italic>APP<\/jats:italic>) and presenilin 1 and 2 (<jats:italic>PSEN1<\/jats:italic> and <jats:italic>PSEN2<\/jats:italic>) have been reported as the pathogenic causes of early-onset AD (EOAD), which accounts for up to 5% of all AD cases. In this study, we screened familiar\/<jats:italic>de novo<\/jats:italic> EOAD (n\u2009=\u200967) samples by next-generation sequencing (NGS) of a 50-gene panel, which included causative and possible pathogenic variants linked to neurodegenerative disorders. Remarkably, three missense mutations in <jats:italic>PSEN1<\/jats:italic> (T119I, G209A, and G417A) and one known variant in <jats:italic>PSEN2<\/jats:italic> (H169N) were discovered in 6% of the cases. Additionally, 67 missense mutations in susceptibility genes for late-onset AD were identified, which may be involved in cholesterol transport, inflammatory response, and \u03b2-amyloid modulation. We identified 70 additional novel and missense variants in other genes, such as <jats:italic>MAPT<\/jats:italic>, <jats:italic>GRN<\/jats:italic>, <jats:italic>CSF1R<\/jats:italic>, and <jats:italic>PRNP<\/jats:italic>, related to neurodegenerative diseases, which may represent overlapping clinical and neuropathological features with AD. Extensive genetic screening of Korean patients with EOAD identified multiple rare variants with potential roles in AD pathogenesis. This study suggests that individuals diagnosed with AD should be screened for other neurodegenerative disease-associated genes. Our findings expand the classic set of genes involved in neurodegenerative pathogenesis, which should be screened for in clinical trials. Main limitation of this study was the absence of functional assessment for possibly and probably pathogenic variants. Additional issues were that we could not perform studies on copy number variants, and we could not verify the segregation of mutations.<\/jats:p>","DOI":"10.1038\/s41598-019-44848-2","type":"journal-article","created":{"date-parts":[[2019,6,10]],"date-time":"2019-06-10T10:03:00Z","timestamp":1560160980000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":104,"title":["Genetic analyses of early-onset Alzheimer\u2019s disease using next generation sequencing"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9937-7865","authenticated-orcid":false,"given":"Vo Van","family":"Giau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Bagyinszky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Soon","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Chul","family":"Youn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8123-6183","authenticated-orcid":false,"given":"Seong Soo A.","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Yun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,6,10]]},"reference":[{"key":"44848_CR1","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jalz.2012.11.007","volume":"9","author":"M Prince","year":"2013","unstructured":"Prince, M. et al. 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