Copy number variants in candidate genes are genetic modifiers of Hirschsprung disease
Open accessAbstract
Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract. The HSCR phenotype is highly variable with respect to gender, length of aganglionosis, familiality and the presence of additional anomalies. By molecular genetic analysis, a minimum of 11 neuro-developmental genes (RET, GDNF, NRTN, SOX10, EDNRB, EDN3, ECE1, ZFHX1B, PHOX2B, KIAA1279, TCF4) are known to harbor rare, high-penetrance mutations that confer a large risk to the bearer. In addition, two other genes (RET, NRG1) harbor common, low-penetrance polymorphisms that contribute only partially to risk and can act as genetic modifiers. To broaden this search, we examined whether a set of 67 proven and candidate HSCR genes harbored additional modifier alleles. In this pilot study, we utilized a custom-designed array CGH with ∼33,000 test probes at an average resolution of ∼185 bp to detect gene-sized or smaller copy number variants (CNVs) within these 67 genes in 18 heterogeneous HSCR patients. Using stringent criteria, we identified CNVs at three loci (MAPK10, ZFHX1B, SOX2) that are novel, involve regulatory and coding sequences of neuro-developmental genes, and show association with HSCR in combination with other congenital anomalies. Additional CNVs are observed under relaxed criteria. Our research suggests a role for CNVs in HSCR and, importantly, emphasizes the role of variation in regulatory sequences. A much larger study will be necessary both for replication and for identifying the full spectrum of small CNV effects.
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Quite a few genes associated with selective sweeps in AMH examined here (among them RET, ZEB2, and SLIT2) have been linked to Hirschsprung disease.
“Quite a few genes associated with selective sweeps in AMH examined here (among them, RET, ZEB2, and SLIT2) have been linked to the disease [81, 82].”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [81]
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Cites
Gene Expression Omnibus: NCBI gene expression and hybridization array data repository
Edgar, R. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.1.207 · Cited by 13,288 · see citing works
The Metabolic and Molecular Bases of Inherited Disease
Scriver, R. C. (1995) · Medical Entomology and Zoology · Cited by 12,101 · see citing works
Finding the missing heritability of complex diseases
Manolio, T. A., Collins, F. S., Cox, N. J., Goldstein, D. B., Hindorff, L. A., Hunter, D. J., McCarthy, M. I., Ramos, E. M., Cardon, L. R., Chakravarti, A., et al. (2009) · Nature · doi:10.1038/nature08494 · Cited by 8,336 · see citing works
Self-citationGregory, P. A., Bert, A. G., Paterson, E. L., Barry, S. C., Tsykin, A., Farshid, G., Vadas, M. A., Khew‐Goodall, Y., & Goodall, G. J. (2008) · Nature Cell Biology · doi:10.1038/ncb1722 · Cited by 3,852 · see citing works
Integrating common and rare genetic variation in diverse human populations
The International HapMap 3 Consortium (2010) · Nature · doi:10.1038/nature09298 · Cited by 3,026 · see citing works
Huber, W., von Heydebreck, A., Sültmann, H., Poustka, A., & Vingron, M. (2002) · Bioinformatics · doi:10.1093/bioinformatics/18.suppl_1.s96 · Cited by 2,440 · see citing works
Circular binary segmentation for the analysis of array-based DNA copy number data
Olshen, A. B., Venkatraman, E. S., Lucito, R., & Wigler, M. H. (2004) · Biostatistics · doi:10.1093/biostatistics/kxh008 · Cited by 2,256 · see citing works
Hirschsprung disease, associated syndromes and genetics: a review
Amiel, J., Emison, E. S., Garcia‐Barceló, M. ‐., Lantieri, F., Burzynski, G. M., Borrego, S., Pelet, A., Arnold, S. M., Miao, X., Griseri, P., et al. (2007) · Journal of Medical Genetics · doi:10.1136/jmg.2007.053959 · Cited by 1,205 · see citing works
Self-citationStructural Variation in the Human Genome and its Role in Disease
Stankiewicz, P., & Lupski, J. R. (2010) · Annual Review of Medicine · doi:10.1146/annurev-med-100708-204735 · Cited by 1,201 · see citing works
LOWESS: A Program for Smoothing Scatterplots by Robust Locally Weighted Regression
Cleveland, W. S. (1981) · The American Statistician · doi:10.2307/2683591 · Cited by 1,182 · see citing works
A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease
Puffenberger, E. G., Hosoda, K., Washington, S. S., Nakao, K., deWit, D., Yanagisawa, M., & Chakravarti, A. (1994) · Cell · doi:10.1016/0092-8674(94)90016-7 · Cited by 883 · see citing works
Self-citationVertebrate neurogenesis is counteracted by Sox1–3 activity
Bylund, M., Andersson, E., Novitch, B. G., & Muhr, J. (2003) · Nature Neuroscience · doi:10.1038/nn1131 · Cited by 825 · see citing works
The ZEB/miR‐200 feedback loop—a motor of cellular plasticity in development and cancer?
Brabletz, S., & Brabletz, T. (2010) · EMBO Reports · doi:10.1038/embor.2010.117 · Cited by 793 · see citing works
A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay
Girirajan, S., Rosenfeld, J. A., Cooper, G. M., Antonacci, F., Siswara, P., Itsara, A., Vives, L., Walsh, T., McCarthy, S. E., Baker, C., et al. (2010) · Nature Genetics · doi:10.1038/ng.534 · Cited by 667 · see citing works
Diversity of Human Copy Number Variation and Multicopy Genes
Sudmant, P. H., Kitzman, J. O., Antonacci, F., Alkan, C., Malig, M., Tsalenko, A., Sampas, N., Bruhn, L., Shendure, J., 1000 Genomes Project, et al. (2010) · Science · doi:10.1126/science.1197005 · Cited by 667 · see citing works
A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk
Emison, E. S., McCallion, A. S., Kashuk, C., Bush, R. T., Grice, E. A., Lin, S., Portnoy, M. E., Cutler, D. J., Green, E. D., & Chakravarti, A. (2005) · Nature · doi:10.1038/nature03467 · Cited by 456 · see citing works
Self-citationMolecular 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 · see citing works
Common deletions and SNPs are in linkage disequilibrium in the human genome
Hinds, D. A., Kloek, A. P., Jen, M., Chen, X., & Frazer, K. A. (2006) · Nature Genetics · doi:10.1038/ng1695 · Cited by 372 · see citing works
Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease
Wakamatsu, N., Yamada, Y., Yamada, K., et al. (2001) · Nature Genetics · doi:10.1038/86860 · Cited by 337 · see citing works
A Chromosomal Deletion Map of Human Malformations
Brewer, C., Holloway, S. M., Zawalnyski, P., et al. (1998) · The American Journal of Human Genetics · doi:10.1086/302041 · Cited by 254 · see citing works
Emison, E. S., Garcia-Barceló, M., Grice, E. A., Lantieri, F., Amiel, J., Burzynski, G. M., Fernández, R. M., Li, H., Kashuk, C., West, K. M., et al. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.06.007 · Cited by 243 · see citing works
Self-citationSOX2 functions in adult neural stem cells
Episkopou, V. (2005) · Trends in Neurosciences · doi:10.1016/j.tins.2005.03.003 · Cited by 242 · see citing works
Brewer, C., Holloway, S. M., Zawalnyski, P., Schinzel, A., & FitzPatrick, D. R. (1999) · The American Journal of Human Genetics · doi:10.1086/302410 · Cited by 217 · see citing works
Gabriel, S., Pelet, A., Hofstra, R. M. W., Angrist, M. H., Salomon, R., Croaker, D., Buys, C. H. C. M., Lyonnet, S., & Chakravarti, A. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.1.268 · Cited by 209 · see citing works
Self-citationA SOX9 Duplication and Familial 46,XX Developmental Testicular Disorder
Cox, J. J., Willatt, L. R., Homfray, T., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmc1010311 · Cited by 197 · see citing works
A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10
Lyonnet, S., Bolino, A., Pelet, A., et al. (1993) · Nature Genetics · doi:10.1038/ng0893-346 · Cited by 194 · see citing works
Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease
García-Barceló, M.-M., Tang, C. S.-M., Ngan, E., Lui, V. C. H., Chen, Y., So, M., Leon, T. Y. Y., Miao, X., Shum, C. K. Y., Liu, F., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0809630105 · Cited by 181 · see citing works
Dathe, K., Kjaer, K. W., Brehm, A., Meinecke, P., Nürnberg, P., Neto, J. C., Brunoni, D., Tommerup, N., Ott, C., Klopocki, E., et al. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.03.001 · Cited by 159 · see citing works
The relative importance of principal and modifying genes in determining some human diseases
Haldane, J. B. S. (1941) · Journal of Genetics · doi:10.1007/bf02983018 · Cited by 134 · see citing works
Heanue, T. A., & Pachnis, V. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602152103 · Cited by 121 · see citing works
Duplications of noncoding elements 5′ of SOX9 are associated with brachydactyly-anonychia
Kurth, I., Klopocki, E., Stricker, S., van Oosterwijk, J. G., Vanek, S., Altmann, J., Santos, H. G., van Harssel, J. J. T., de Ravel, T. J. L., Wilkie, A. O. M., et al. (2009) · Nature Genetics · doi:10.1038/ng0809-862 · Cited by 116 · see citing works
Gene copy number variation and common human disease
Fanciulli, M., Petretto, E. G., & Aitman, T. J. (2009) · Clinical Genetics · doi:10.1111/j.1399-0004.2009.01342.x · Cited by 111 · see citing works
The ENCODE Project at UC Santa Cruz
Thomas, D. J., Rosenbloom, K. R., Clawson, H., Hinrichs, A. S., Trumbower, H., Raney, B. J., Karolchik, D., Barber, G. P., Harte, R., Hillman‐Jackson, J., et al. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl1017 · Cited by 95 · see citing works
Lower, K. M., Hughes, J. R., De Gobbi, M., Henderson, S., Viprakasit, V., Fisher, C., Goriely, A., Ayyub, H., Sloane-Stanley, J., Vernimmen, D., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909331106 · Cited by 92 · see citing works
Epistatic interactions with a common hypomorphicRET allele in syndromic Hirschsprung disease
de Pontual, L., Pelet, A., Clément‐Ziza, M., Trochet, D., Antonarakis, S. E., Attié‐Bitach, T., Beales, P. L., Blouin, J.-L., Moal, F., Dollfus, H., et al. (2007) · Human Mutation · doi:10.1002/humu.20517 · Cited by 83 · see citing works
Copy number variation modifies expression time coursesPreprint
Chaignat, E., Ait‐Yahya, E., Hor, C. N., Chrast, J., Schütz, F., Pradervand, S., & Reymond, A. (2010) · Genome Research · doi:10.1101/gr.112748.110 · Cited by 63 · see citing works
Arnold, S. M., Pelet, A., Amiel, J., et al. (2009) · Human Mutation · doi:10.1002/humu.20944 · Cited by 60 · see citing works
High resolution discovery and confirmation of copy number variants in 90 Yoruba Nigerians
Matsuzaki, H., Wang, P., Hu, J., Rava, R., & Fu, G. K. (2009) · Genome biology · doi:10.1186/gb-2009-10-11-r125 · Cited by 59 · see citing works
Neidhart, S., Antonsson, B. E., Gilliéron, C., Vilbois, F., Grenningloh, G., & Arkinstall, S. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)03090-3 · Cited by 35 · see citing works
Serra, A., Görgens, H., Alhadad, K., et al. (2009) · Annals of Human Genetics · doi:10.1111/j.1469-1809.2008.00503.x · Cited by 11 · see citing works
Núñez‐Torres, R., Fernández, R. M., López-Alonso, M., et al. (2009) · BMC Medical Genetics · doi:10.1186/1471-2350-10-119 · Cited by 8 · see citing works
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Self-domestication in Homo sapiens: Insights from comparative genomics
Theofanopoulou, C., Gastaldon, S., O’Rourke, T., Samuels, B. D., Messner, A., Martins, P. T., Delogu, F., Alamri, S., & Boeckx, C. (2017) · PLOS ONE · doi:10.1371/journal.pone.0185306 · Cited by 174 · see citing works
Globularization and domestication.
Benítez-Burraco, A., Theofanopoulou, C., & Boeckx, C. (2018) · Topoi · doi:10.1007/s11245-016-9399-7 · Cited by 42 · see citing works
- Authors
- Jiang, Q., Ho, Y.-Y., Hao, L., Nichols Berrios, C., & Chakravarti, A.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Chakravarti, Aravinda
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-06-21
- Volume
- 6
- Issue
- 6
- Pages
- e21219
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3119685
- OpenAlex
- W2024091637
- Cited by
- 62
- References
- 41
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 10 · 2016: 7 · 2015: 4 · 2014: 3 · 2013: 7 · 2012: 8
- FWCI
- 6.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Scholar Commons (University of South Carolina) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (HD28088)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37 HD28088, R37HD028088)
- Topics
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Surgery › Intestinal Malrotation and Obstruction Disorders
- Keywords
- Hirschsprung disease, copy number variation, genetic modifiers, candidate genes, neurocristopathy, aganglionosis, MAPK10, ZEB2, SOX2, congenital malformations, RET, neuregulin-1, array comparative genomic hybridization
- MeSH terms
- Zinc Finger E-box Binding Homeobox 2, Female, Hirschsprung Disease, Humans, Infant, Newborn, Male, Phenotype, Repressor Proteins, Homeodomain Proteins, Mitogen-Activated Protein Kinase 10, Comparative Genomic Hybridization, SOXB1 Transcription Factors, DNA Copy Number Variations
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