{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:49:58Z","timestamp":1786978198906,"version":"build-2736575974"},"reference-count":52,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T00:00:00Z","timestamp":1576108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008893","name":"University of Iowa","doi-asserted-by":"publisher","award":["Dance Marathon"],"award-info":[{"award-number":["Dance Marathon"]}],"id":[{"id":"10.13039\/100008893","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32DK112751\u201001"],"award-info":[{"award-number":["T32DK112751\u201001"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The 22q11.2 deletion syndrome (22q11.2DS) is the most common contiguous microdeletion affecting humans and exhibits extreme phenotypic heterogeneity. Patients can manifest any combination of comorbidities including congenital heart disease, hypoparathyroidism, cleft palate, kidney abnormalities, neurodevelopmental disorders, and immune dysfunction. Immunodeficiency is present in the majority of patients with 22q11.2DS and is the second leading cause of death in these patients. Knowing the genetic determinants of immune dysfunction will aid in prognostication and potentially novel treatments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed exome sequencing and gene\u2010based variant association analysis on 31 deeply phenotyped individuals with the canonical 3Mb 22q11.2 deletion to identify what genes outside the 22q11.2 locus may be modifying the immune dysregulated phenotype. Immunophenotyping was performed using preexisting medical data and a novel scoring system developed from numerous clinical laboratory values including immunoglobulin levels, lymphocyte transformation to antigens (LTA), lymphocyte transformation to mitogens (LTM), and peripheral blood flow cytometry. Immunophenotypic scoring was validated against newborn screening T\u2010cell receptor excision circle (TREC) results.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Rare DNA variants in transcriptional regulators involved in retinoic acid signaling (\n                      <jats:italic>NCOR2,<\/jats:italic>\n                      OMIM *600848 and\n                      <jats:italic>EP300<\/jats:italic>\n                      , OMIM *602700) were found to be associated with immunophenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The expression of\n                      <jats:italic>TBX1<\/jats:italic>\n                      , which seems to confer the major phenotypic features of 22q11.2DS, is regulated via retinoic acid signaling, and alterations in retinoic acid signaling during embryonic development can lead to phenocopies of 22q11.2DS. These observations support the hypothesis that genetic modifiers outside the microdeletion locus may influence the immune function in 22q11.2DS patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mgg3.1057","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T19:11:03Z","timestamp":1576177863000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Candidate modifier genes for immune function in 22q11.2 deletion syndrome"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6450-0918","authenticated-orcid":false,"given":"Catherina T.","family":"Pinnaro","sequence":"first","affiliation":[{"name":"Stead Family Department of Pediatrics Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis","family":"Henry","sequence":"additional","affiliation":[{"name":"Iowa State Hygienic Laboratory Coralville IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather J.","family":"Major","sequence":"additional","affiliation":[{"name":"Stead Family Department of Pediatrics Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mrutyunjaya","family":"Parida","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy E.","family":"DesJardin","sequence":"additional","affiliation":[{"name":"Iowa State Hygienic Laboratory Coralville IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Manak","sequence":"additional","affiliation":[{"name":"Departments of Biology and Pediatrics University of Iowa Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9279-356X","authenticated-orcid":false,"given":"Benjamin W.","family":"Darbro","sequence":"additional","affiliation":[{"name":"Stead Family Department of Pediatrics Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142905.hg0720s76"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-017-0403-9"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.112.1.101"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.117.1125"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.4161\/epi.6.8.16065"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38597"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.35.9.789-a"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1597\/05-070.1"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.09.002"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1086\/302343"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.32.9.746"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-015-0153-5"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.10.013"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/circgenetics.116.001690"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.03.003"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg4017"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21743"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61152"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/85845"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.115345"},{"issue":"9","key":"e_1_2_9_23_1","first-page":"721","article-title":"Microdeletion 22q11.2: Clinical data and deletion size","volume":"36","author":"Kerstjens\u2010Frederikse W. 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