title: The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies.
abstract: 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.
authors: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Jan O
authors: JO
authors: Korbel
authors: Tal
authors: T
authors: Tirosh-Wagner
authors: Alexander Eckehart
authors: AE
authors: Urban
authors: Xiao-Ning
authors: XN
authors: Chen
authors: Maya
authors: M
authors: Kasowski
authors: Li
authors: L
authors: Dai
authors: Fabian
authors: F
authors: Grubert
authors: Chandra
authors: C
authors: Erdman
authors: Michael C
authors: MC
authors: Gao
authors: Ken
authors: K
authors: Lange
authors: Eric M
authors: EM
authors: Sobel
authors: Gillian M
authors: GM
authors: Barlow
authors: Arthur S
authors: AS
authors: Aylsworth
authors: Nancy J
authors: NJ
authors: Carpenter
authors: Robin Dawn
authors: RD
authors: Clark
authors: Monika Y
authors: MY
authors: Cohen
authors: Eric
authors: E
authors: Doran
authors: Tzipora
authors: T
authors: Falik-Zaccai
authors: Susan O
authors: SO
authors: Lewin
authors: Ira T
authors: IT
authors: Lott
authors: Barbara C
authors: BC
authors: McGillivray
authors: John B
authors: JB
authors: Moeschler
authors: Mark J
authors: MJ
authors: Pettenati
authors: Siegfried M
authors: SM
authors: Pueschel
authors: Kathleen W
authors: KW
authors: Rao
authors: Lisa G
authors: LG
authors: Shaffer
authors: Mordechai
authors: M
authors: Shohat
authors: Alexander J
authors: AJ
authors: Van Riper
authors: Dorothy
authors: D
authors: Warburton
authors: Sherman
authors: S
authors: Weissman
authors: Mark B
authors: MB
authors: Gerstein
authors: Michael
authors: M
authors: Snyder
authors: Julie R
authors: JR
authors: Korenberg
mesh_terms: D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D004314:Down Syndrome / Q000235:genetics*; D006801:Humans; D007223:Infant; D015201:Meta-Analysis as Topic; D010641:Phenotype; D014314:Trisomy / Q000235:genetics*