The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index.
The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies
Open accessAbstract
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.
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“a disorder in which an early onset form of AD invariably develops due mainly to a third copy of APP present on trisomic chromosome 21 (Korbel et al., 2009;Doran et al., 2017;Colacurcio et al., 2018).”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Korbel et al., 2009
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“Alternatively, a targeted gene or set of genes hypothesized to have a major influence on a phenotype due to overexpression in DS may be a therapeutic focus (Korbel et al., 2009; Lyle et al., 2009).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Korbel et al., 2009
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Global variation in copy number in the human genome
Redon, R., Ishikawa, S., Fitch, K. R., Feuk, L., Perry, G. H., Andrews, T. D., Fiegler, H., Shapero, M. H., Carson, A. R., Chen, W., et al. (2006) · Nature · doi:10.1038/nature05329 · Cited by 4,377
Detection of large-scale variation in the human genome
Iafrate, A. J., Feuk, L., Rivera, M. N., Listewnik, M. L., Donahoe, P. K., Qi, Y., Scherer, S. W., & Lee, C. (2004) · Nature Genetics · doi:10.1038/ng1416 · Cited by 2,892
Large-scale copy number polymorphism in the human genome
Sebat, J., Lakshmi, B., Troge, J., Alexander, J., Young, J., Lundin, P., Månér, S., Massa, H., Walker, M., Chi, M., et al. (2004) · Science · doi:10.1126/science.1098918 · Cited by 2,557
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Rovelet‐Lecrux, A., Hannequin, D., Raux, G., Meur, N. L., Laquerrière, A., Vital, A., Dumanchin‐Njock, C., Feuillette, S., Brice, A., Vercelletto, M., et al. (2005) · Nature Genetics · doi:10.1038/ng1718 · Cited by 1,284
Paired-End Mapping Reveals Extensive Structural Variation in the Human Genome
Korbel, J. O., Urban, A. E., Affourtit, J. P., Godwin, B., Grubert, F., Simons, J. F., Kim, P. M., Palejev, D., Carriero, N. J., Du, L., et al. (2007) · Science · doi:10.1126/science.1149504 · Cited by 1,163
Self-citationDown syndrome phenotypes: the consequences of chromosomal imbalance.
Korenberg, J. R., Chen, X. N., Schipper, R. D., Sun, Z., Gonsky, R., Gerwehr, S., Carpenter, N. J., Däumer, C., Dignan, P. S. J., & Distèche, C. M. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.11.4997 · Cited by 784
Self-citationNFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21
Arron, J. R., Winslow, M. M., Polleri, A., Chang, C.-P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., et al. (2006) · Nature · doi:10.1038/nature04678 · Cited by 698
A new non-linear normalization method for reducing variability in DNA microarray experiments
Workman, C. T., Jensen, L. J., Jarmer, H. Ø., Berka, R. M., Gautier, L., Nielsen, H. B., Saxild, H. H., Nielsen, C. H., Brunak, S., & Knudsen, S. (2002) · Genome biology · doi:10.1186/gb-2002-3-9-research0048 · Cited by 531
Molecular Mapping of Twenty-Four Features of Down Syndrome on Chromosome 21
Delabar, J. M., Theophile, D., Rahmani, Z., Chettouh, Z., Blouin, J., Prieur, M., Noel, B., & Sinet, P. (1993) · European Journal of Human Genetics · doi:10.1159/000472398 · Cited by 454
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Metadata
- Authors
- Korbel, J. O., Tirosh-Wagner, T., Urban, A. E., Chen, X.-N., Kasowski, M., Dai, L., Grubert, F., Erdman, C., Gao, M. C., Lange, K., Sobel, E. M., Barlow, G. M., Aylsworth, A. S., Carpenter, N. J., Clark, R. D., Cohen, M. Y., Doran, E., Falik-Zaccai, T., Lewin, S. O., Lott, I. T., McGillivray, B. C., Moeschler, J. B., Pettenati, M. J., Pueschel, S. M., Rao, K. W., Shaffer, L. G., Shohat, M., Van Riper, A. J., Warburton, D., Weissman, S., Gerstein, M. B., Snyder, M., & Korenberg, J. R.
- Affiliations
- European Bioinformatics Institute (GB)
- Medical Genetics Institute, Cedars–Sinai Medical Center, Los Angeles, CA 90048;
- Yale University (US)
- Cedars-Sinai Medical Center (US)
- University of California, Los Angeles (US)
- University of North Carolina at Chapel Hill (US)
- Center for Genetic Testing, Tulsa, OK 74136;
- Loma Linda University Medical Center (US)
- Department of Genetics, Kinderzentrum Munich, 81377 Munich, Germany;
- University of California, Irvine Medical Center (US)
- Institute of Human Genetics, Western Galilee Hospital, Nahariya 22100, Israel;
- University of Utah (US)
- University of British Columbia (CA)
- Dartmouth–Hitchcock Medical Center (US)
- Wake Forest University Health Sciences (US)
- Rhode Island Hospital (US)
- Signature Genomic Laboratories, Spokane, WA 99207;
- Tel Aviv University (IL)
- Genetics Department, Kaiser Permanente Medical Offices, Sacramento, CA 95815;
- Columbia University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-07-21
- Volume
- 106
- Issue
- 29
- Pages
- 12031-12036
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2709665
- OpenAlex
- W1964683842
- Cited by
- 399
- References
- 47
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 16 · 2023: 20 · 2022: 22 · 2021: 27 · 2020: 24 · 2019: 21 · 2018: 11 · 2017: 14 · 2016: 26 · 2015: 28 · 2014: 28 · 2013: 30 · 2012: 38
- FWCI
- 34.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- U.S. Department of Energy
- European Commission
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM007205)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
- Keywords
- Down syndrome, chromosome 21, gene mapping, copy number variation, congenital heart disease, Hirschsprung disease, duodenal stenosis, acute megakaryoblastic leukemia, transient myeloproliferative disorder, intellectual disability, Alzheimer's disease, DSCR1, DYRK1A, APP, etiology
- MeSH terms
- Chromosome Mapping, Chromosomes, Human, Pair 21, Down Syndrome, Humans, Infant, Phenotype, Trisomy, Meta-Analysis as Topic
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