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To determine the association between differential gene expression, epigenetic state, and phenotypic variation among people with A-T, we performed transcriptional and genome-wide DNA methylation profiling in patients with mild and classic A-T progression as well as healthy controls. RNA and genomic DNA were isolated from peripheral blood mononuclear cells for transcriptional and DNA methylation profiling with RNA-sequencing and modified reduced representation bisulfite sequencing, respectively. We identified 555 genes that were differentially expressed among the control, mild A-T, and classic A-T groups. Genome-wide DNA methylation profiling revealed differential promoter methylation in<jats:italic>cis<\/jats:italic>with 146 of these differentially expressed genes. Functional enrichment analysis identified significant enrichment in immune, growth, and apoptotic pathways among the methylation-regulated genes. Regardless of clinical phenotype, all A-T participants exhibited downregulation of critical genes involved in B cell function (<jats:italic>PAX5<\/jats:italic>,<jats:italic>CD79A<\/jats:italic>,<jats:italic>CD22<\/jats:italic>, and<jats:italic>FCRL1<\/jats:italic>) and upregulation of several genes associated with senescence and malignancy, including<jats:italic>SERPINE1<\/jats:italic>. These findings indicate that gene expression differences may be associated with phenotypic variability and suggest that DNA methylation regulates expression of critical immune response genes in people with A-T.<\/jats:p>","DOI":"10.1038\/s41598-020-64514-2","type":"journal-article","created":{"date-parts":[[2020,5,4]],"date-time":"2020-05-04T10:05:01Z","timestamp":1588586701000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["DNA methylation and gene expression signatures are associated with ataxia-telangiectasia phenotype"],"prefix":"10.1038","volume":"10","author":[{"given":"Sharon A.","family":"McGrath-Morrow","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland","family":"Ndeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn A.","family":"Helmin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Basil","family":"Khuder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cynthia","family":"Rothblum-Oviatt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph M.","family":"Collaco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Wright","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul A.","family":"Reyfman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Howard M.","family":"Lederman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin D.","family":"Singer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,5,4]]},"reference":[{"key":"64514_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-016-0543-7","volume":"11","author":"C Rothblum-Oviatt","year":"2016","unstructured":"Rothblum-Oviatt, C. et al. 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