The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies

Jan O. Korbel, Tal Tirosh-Wagner, Alexander Eckehart Urban, Xiao Ning Chen, Maya Kasowski, Li Dai, Fabian Grubert, Chandra Erdman, Michael C. Gao, Ken Lange, Eric M. Sobel, Gillian M. Barlow, Arthur S. Aylsworth, Nancy J. Carpenter, Robin Dawn Clark, Monika Y. Cohen, Eric Doran, Tzipora Falik-Zaccai, Susan O. Lewin, Ira T. LottBarbara C. McGillivray, John B. Moeschler, Mark J. Pettenati, Siegfried M. Pueschel, Kathleen W. Rao, Lisa G. Shaffer, Mordechai Shohat, Alexander J. Van Riper, Dorothy Warburton, Sherman Weissman, Mark B. Gerstein, Michael Snyder, Julie R. Korenberg

Research output: Contribution to journalArticlepeer-review

321 Scopus citations


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 1.8-16.3 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 <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 - i.e., the presence of a single DS consensus region and the sufficiency of DSCR1 and DYRK1A, or APP, 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.

Original languageEnglish
Pages (from-to)12031-12036
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number29
StatePublished - 21 Jul 2009
Externally publishedYes


FundersFunder number
National Institute of General Medical SciencesT32GM007205


    • Congenital heart disease
    • Copy number variants
    • Genomic structural variation
    • Human genome
    • Leukemia


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