{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:09:58Z","timestamp":1791216598146,"version":"4.1.0"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"29","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,7,21]]},"abstract":"<jats:p>\n                    Down syndrome (DS), or trisomy 21, is a common disorder associated with several complex clinical phenotypes. Although several hypotheses have been put forward, it is unclear as to whether particular gene loci on chromosome 21 (HSA21) are sufficient to cause DS and its associated features. Here we present a high-resolution genetic map of DS phenotypes based on an analysis of 30 subjects carrying rare segmental trisomies of various regions of HSA21. By using state-of-the-art genomics technologies we mapped segmental trisomies at exon-level resolution and identified discrete regions of 1.8\u201316.3 Mb likely to be involved in the development of 8 DS phenotypes, 4 of which are congenital malformations, including acute megakaryocytic leukemia, transient myeloproliferative disorder, Hirschsprung disease, duodenal stenosis, imperforate anus, severe mental retardation, DS-Alzheimer Disease, and DS-specific congenital heart disease (DSCHD). Our DS-phenotypic maps located DSCHD to a &lt;2-Mb interval. Furthermore, the map enabled us to present evidence against the necessary involvement of other loci as well as specific hypotheses that have been put forward in relation to the etiology of DS\u2014i.e., the presence of a single DS consensus region and the sufficiency of\n                    <jats:italic>DSCR1<\/jats:italic>\n                    and\n                    <jats:italic>DYRK1A<\/jats:italic>\n                    , or\n                    <jats:italic>APP<\/jats:italic>\n                    , in causing several severe DS phenotypes. Our study demonstrates the value of combining advanced genomics with cohorts of rare patients for studying DS, a prototype for the role of copy-number variation in complex disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0813248106","type":"journal-article","created":{"date-parts":[[2009,7,13]],"date-time":"2009-07-13T21:53:42Z","timestamp":1247522022000},"page":"12031-12036","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":360,"title":["The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies"],"prefix":"10.1073","volume":"106","author":[{"given":"Jan O.","family":"Korbel","sequence":"first","affiliation":[{"name":"Departments of aMolecular Biophysics and Biochemistry,"},{"name":"European Molecular Biology Laboratory, 69117 Heidelberg, Germany;"},{"name":"European Molecular Biology Laboratory (EMBL) Outstation Hinxton, EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tal","family":"Tirosh-Wagner","sequence":"additional","affiliation":[{"name":"Medical Genetics Institute, Cedars\u2013Sinai Medical Center, Los Angeles, CA 90048;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander Eckehart","family":"Urban","sequence":"additional","affiliation":[{"name":"Molecular, Cellular, and Developmental Biology, and"},{"name":"Genetics, Yale University School of Medicine, New Haven, CT 06520;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Ning","family":"Chen","sequence":"additional","affiliation":[{"name":"Medical Genetics Institute, Cedars\u2013Sinai Medical Center, Los Angeles, CA 90048;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Kasowski","sequence":"additional","affiliation":[{"name":"Molecular, Cellular, and Developmental Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Dai","sequence":"additional","affiliation":[{"name":"Medical Genetics Institute, Cedars\u2013Sinai Medical Center, Los Angeles, CA 90048;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Grubert","sequence":"additional","affiliation":[{"name":"Genetics, Yale University School of Medicine, New Haven, CT 06520;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandra","family":"Erdman","sequence":"additional","affiliation":[{"name":"Department of Statistics, Yale University, New Haven, CT 06520;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Gao","sequence":"additional","affiliation":[{"name":"Medical Genetics Institute, Cedars\u2013Sinai Medical Center, Los Angeles, CA 90048;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Lange","sequence":"additional","affiliation":[{"name":"Departments of hHuman Genetics, and"},{"name":"Biomathematics, University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Sobel","sequence":"additional","affiliation":[{"name":"Departments of hHuman Genetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian M.","family":"Barlow","sequence":"additional","affiliation":[{"name":"Medical Genetics Institute, Cedars\u2013Sinai Medical Center, Los Angeles, CA 90048;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur S.","family":"Aylsworth","sequence":"additional","affiliation":[{"name":"Departments of jPediatrics and"},{"name":"Genetics, University of North Carolina, Chapel Hill, NC 27599;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy J.","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Center for Genetic Testing, Tulsa, OK 74136;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin Dawn","family":"Clark","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA 92354;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika Y.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Genetics, Kinderzentrum Munich, 81377 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Doran","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Neurology, Irvine Medical Center, University of California, Orange, CA 92868;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzipora","family":"Falik-Zaccai","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Western Galilee Hospital, Nahariya 22100, Israel;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan O.","family":"Lewin","sequence":"additional","affiliation":[{"name":"Section of Clinical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84132;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ira T.","family":"Lott","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Neurology, Irvine Medical Center, University of California, Orange, CA 92868;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara C.","family":"McGillivray","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Women's Health Centre, University of British Columbia, Vancouver, BC, Canada V6H 3V5;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John B.","family":"Moeschler","sequence":"additional","affiliation":[{"name":"Section of Clinical Genetics, Department of Pediatrics, Dartmouth\u2013Hitchcock Medical Center, Lebanon, NH 03756;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Pettenati","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Section on Medical Genetics, Wake Forest University School of Medicine, Winston-Salem, NC 27157;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siegfried M.","family":"Pueschel","sequence":"additional","affiliation":[{"name":"Child Development Center, Rhode Island Hospital, Providence RI 02902;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen W.","family":"Rao","sequence":"additional","affiliation":[{"name":"Departments of jPediatrics and"},{"name":"Genetics, University of North Carolina, Chapel Hill, NC 27599;"},{"name":"Department of Pathology, University of North Carolina, Chapel Hill, NC 27514;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa G.","family":"Shaffer","sequence":"additional","affiliation":[{"name":"Signature Genomic Laboratories, Spokane, WA 99207;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mordechai","family":"Shohat","sequence":"additional","affiliation":[{"name":"Recanati Institute for Medical Genetics, Rabin Medical Center, Tel Aviv University, Petah Tikva, 49100 Israel;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J.","family":"Van Riper","sequence":"additional","affiliation":[{"name":"Genetics Department, Kaiser Permanente Medical Offices, Sacramento, CA 95815;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothy","family":"Warburton","sequence":"additional","affiliation":[{"name":"Department of Genetics and Development, Columbia University, New York, NY 10032;"},{"name":"Children's Hospital of New York, New York, NY 10032; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherman","family":"Weissman","sequence":"additional","affiliation":[{"name":"Genetics, Yale University School of Medicine, New Haven, CT 06520;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark B.","family":"Gerstein","sequence":"additional","affiliation":[{"name":"Departments of aMolecular Biophysics and Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Snyder","sequence":"additional","affiliation":[{"name":"Departments of aMolecular Biophysics and Biochemistry,"},{"name":"Molecular, Cellular, and Developmental Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie R.","family":"Korenberg","sequence":"additional","affiliation":[{"name":"Medical Genetics Institute, Cedars\u2013Sinai Medical Center, Los Angeles, CA 90048;"},{"name":"Departments of hHuman Genetics, and"},{"name":"Department of Pediatrics, Center for Integrated Neurosciences and Human Behavior, The Brain Institute, University of Utah, Salt Lake City, UT 84108"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,7,21]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1017\/CBO9780511529702.014","volume-title":"The Consequences Of Chromosome Imbalance Principles, Mechanisms, and Models","author":"Epstein CJ","year":"1986","unstructured":"CJ Epstein The Consequences Of Chromosome Imbalance Principles, Mechanisms, and Models, eds PW Barlow, PB Green, CC Wylie (Cambridge Univ Press, New York), pp. 253\u2013323 (1986)."},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.11.4997"},{"key":"e_1_3_3_3_2","first-page":"91","article-title":"Down syndrome: Toward a molecular definition of the phenotype","volume":"7","author":"Korenberg JR","year":"1990","unstructured":"JR Korenberg, et al., Down syndrome: Toward a molecular definition of the phenotype. Am J Med Genet Suppl 7, 91\u201397 (1990).","journal-title":"Am J Med Genet Suppl"},{"key":"e_1_3_3_4_2","first-page":"99","article-title":"Down's syndrome. The possibility of a pathogenetic segment on chromosome no. 21","volume":"21","author":"Niebuhr E","year":"1974","unstructured":"E Niebuhr, Down's syndrome. The possibility of a pathogenetic segment on chromosome no. 21. Humangenetik 21, 99\u2013101 (1974).","journal-title":"Humangenetik"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.15.5958"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04678"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.21433"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1159\/000472398"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2006.047373"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/00125817-200103000-00002"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1159\/000133962"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.9.10.994"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0511340103"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0703834104"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1416"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1149504"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05329"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1098918"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19980605)77:5<431::AID-AJMG15>3.0.CO;2-J"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2003.10.036"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm086"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1114535"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng868"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.2.227"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(00)00532-1"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-0147"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-2264(199809)23:1<61::AID-GCC9>3.0.CO;2-4"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0511150103"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1718"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.5.5.427"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1159\/000133017"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2000-1-2-reviews0002"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/0888-7543(89)90095-5"},{"key":"e_1_3_3_34_2","first-page":"316","article-title":"Physical mapping around the Alzheimer disease locus on the proximal long arm of chromosome 21","volume":"46","author":"Owen MJ","year":"1990","unstructured":"MJ Owen, LA James, JA Hardy, R Williamson, AM Goate, Physical mapping around the Alzheimer disease locus on the proximal long arm of chromosome 21. Am J Hum Genet 46, 316\u2013322 (1990).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1997.4657"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-7799(92)90163-P"},{"key":"e_1_3_3_37_2","first-page":"294","article-title":"Down syndrome: Molecular mapping of the congenital heart disease and duodenal stenosis","volume":"50","author":"Korenberg JR","year":"1992","unstructured":"JR Korenberg, C Bradley, CM Disteche, Down syndrome: Molecular mapping of the congenital heart disease and duodenal stenosis. Am J Hum Genet 50, 294\u2013302 (1992).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2002-3-9-research0048"},{"key":"e_1_3_3_39_2","first-page":"263","article-title":"Segmental trisomy of murine chromosome 16: A new model system for studying Down syndrome","volume":"360","author":"Davisson MT","year":"1990","unstructured":"MT Davisson, C Schmidt, EC Akeson, Segmental trisomy of murine chromosome 16: A new model system for studying Down syndrome. Prog Clin Biol Res 360, 263\u2013280 (1990).","journal-title":"Prog Clin Biol Res"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1098992"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.11.6256"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2008.214"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2007-8-5-r91"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0813248106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T16:53:23Z","timestamp":1653324803000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0813248106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,7,21]]},"references-count":43,"journal-issue":{"issue":"29","published-print":{"date-parts":[[2009,7,21]]}},"alternative-id":["10.1073\/pnas.0813248106"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0813248106","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,7,21]]},"assertion":[{"value":"2008-12-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-07-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}