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