Cited by 334Genomic variations and chromosomal abnormalitiesGenome Rearrangement AlgorithmsGenomics and Rare Diseases

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

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Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee +141 more·2017·Nature Genetics

Abstract

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.

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  • A large survey of balanced chromosomal abnormalities in congenital anomaly patients found TAD disruption around known syndrome-linked loci in 7.3% of cases.

    “A large-scale survey of balanced chromosomal abnormalities in patients with congenital anomalies revealed disruption of TADs encompassing known syndrome-linked loci in 7.3% of cases 65 ,”

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Authors
Redin, C., Brand, H., Collins, R. L., Kammin, T., Mitchell, E., Hodge, J. C., Hanscom, C., Pillalamarri, V., Seabra, C. M., Abbott, M.-A., Abdul-Rahman, O. A., Aberg, E., Adley, R., Alcaraz-Estrada, S. L., Alkuraya, F. S., An, Y., Anderson, M.-A., Antolik, C., Anyane-Yeboa, K., Atkin, J. F., Bartell, T., Bernstein, J. A., Beyer, E., Blumenthal, I., Bongers, E. M. H. F., Brilstra, E. H., Brown, C. W., Brüggenwirth, H. T., Callewaert, B., Chiang, C., Corning, K., Cox, H., Cuppen, E., Currall, B. B., Cushing, T., David, D., Deardorff, M. A., Dheedene, A., D'Hooghe, M., de Vries, B. B. A., Earl, D. L., Ferguson, H. L., Fisher, H., FitzPatrick, D. R., Gerrol, P., Giachino, D., Glessner, J. T., Gliem, T., Grady, M., Graham, B. H., Griffis, C., Gripp, K. W., Gropman, A. L., Hanson-Kahn, A., Harris, D. J., Hayden, M. A., Hill, R., Hochstenbach, R., Hoffman, J. D., Hopkin, R. J., Hubshman, M. W., Innes, A. M., Irons, M., Irving, M., Jacobsen, J. C., Janssens, S., Jewett, T., Johnson, J. P., Jongmans, M. C., Kahler, S. G., Koolen, D. A., Korzelius, J., Kroisel, P. M., Lacassie, Y., Lawless, W., Lemyre, E., Leppig, K., Levin, A. V., Li, H., Li, H., Liao, E. C., Lim, C., Lose, E. J., Lucente, D., Macera, M. J., Manavalan, P., Mandrile, G., Marcelis, C. L., Margolin, L., Mason, T., Masser-Frye, D., McClellan, M. W., Mendoza, C. J. Z., Menten, B., Middelkamp, S., Mikami, L. R., Moe, E., Mohammed, S., Mononen, T., Mortenson, M. E., Moya, G., Nieuwint, A. W., Ordulu, Z., Parkash, S., Pauker, S. P., Pereira, S., Perrin, D., Phelan, K., Aguilar, R. E. P., Poddighe, P. J., Pregno, G., Raskin, S., Reis, L., Rhead, W., Rita, D., Renkens, I., Roelens, F., Ruliera, J., Rump, P., Schilit, S. L. P., Shaheen, R., Sparkes, R., Spiegel, E., Stevens, B., Stone, M. R., Tagoe, J., Thakuria, J. V., van Bon, B. W., van de Kamp, J., van Der Burgt, I., van Essen, T., van Ravenswaaij-Arts, C. M., van Roosmalen, M. J., Vergult, S., Volker-Touw, C. M. L., Warburton, D. P., Waterman, M. J., Wiley, S., Wilson, A., Yerena-de Vega, M. D. L. C. A., Zori, R. T., Levy, B., Brunner, H. G., de Leeuw, N., Kloosterman, W. P., Thorland, E. C., Morton, C. C., Gusella, J. F., & Talkowski, M. E.
Affiliations
  • Broad Institute (US)
  • Brigham and Women's Hospital (US)
  • Mayo Clinic (US)
  • Cedars-Sinai Medical Center (US)
  • Baystate Medical Center (US)
  • University of Mississippi Medical Center (US)
  • Izaak Walton Killam Health Centre (CA)
  • Massachusetts General Hospital (US)
  • King Faisal Specialist Hospital & Research Centre (SA)
  • Shanghai Medical College of Fudan University (CN)
  • Nationwide Children's Hospital (US)
  • Kaiser Permanente (US)
  • Stanford Medicine (US)
  • Children's Hospital of Wisconsin (US)
  • Radboud University Nijmegen (NL)
  • University Medical Center Utrecht (NL)
  • Baylor College of Medicine (US)
  • Erasmus MC (NL)
  • Ghent University (BE)
  • Greenwood Genetic Center (US)
  • Birmingham Women's Hospital (GB)
  • University of New Mexico (US)
  • Children's Hospital of Philadelphia (US)
  • Western General Hospital (GB)
  • University of Turin (IT)
  • ProHealth Care (US)
  • Thomas Jefferson University (US)
  • Children's National (US)
  • Boston Children's Hospital (US)
  • Auckland City Hospital (NZ)
  • Boston Medical Center (US)
  • Cincinnati Children's Hospital Medical Center (US)
  • Tel Aviv University (IL)
  • University of Calgary (CA)
  • American Board of Medical Specialties (US)
  • Guy's Hospital (GB)
  • University of Auckland (NZ)
  • Wake Forest University Health Sciences (US)
  • Shodair Children's Hospital (US)
  • Arkansas Children's Hospital (US)
  • Medical University of Graz (AT)
  • Louisiana State University (US)
  • Centre Hospitalier Universitaire Sainte-Justine (CA)
  • Group Health Cooperative (US)
  • Nanjing Medical University (CN)
  • Harvard University (US)
  • University of Alabama at Birmingham (US)
  • NewYork–Presbyterian Hospital (US)
  • Madigan Army Medical Center (US)
  • Pontifícia Universidade Católica do Paraná (BR)
  • Kuopio University Hospital (FI)
  • Novant Health (US)
  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
  • Dalhousie University (CA)
  • Tulane University (US)
  • University of Aberdeen (GB)
  • Medical College of Wisconsin (US)
  • AZ Delta (BE)
  • University Medical Center Groningen (NL)
  • Columbia University Irving Medical Center (US)
  • The University of Texas Health Science Center at Houston (US)
  • Alberta Health Services (CA)
  • Eastern Nazarene College (US)
  • University of Florida (US)
  • Columbia University (US)
Corresponding author
Talkowski, Michael E
Venue
Nature Genetics
Published
2016-11-14
Volume
49
Issue
1
Pages
36-45
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W2551666886
Cited by
334
References
88
Citations by year
2026: 14 · 2025: 23 · 2024: 21 · 2023: 31 · 2022: 31 · 2021: 31 · 2020: 50 · 2019: 45 · 2018: 66 · 2017: 21
FWCI
35.44
Type
journal article
Language
en
Open access
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, other-oa)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • Research Explorer (The University of Manchester) (publishedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
  • Kent Academic Repository (University of Kent) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
  • UNM’s Digital Repository (University of New Mexico) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
  • Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
  • Utrecht University Repository (Utrecht University) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • National Science Foundation (1144152)
  • March of Dimes Foundation (6-FY15-255)
  • Philippe Foundation
  • Suzhou Key Medical Center
  • European Commission (51,52, 70,71, 34,35, 25,26)
  • Royal Society Te Apārangi
  • Government of Jiangsu Province (BL2013019)
  • Fonds Wetenschappelijk Onderzoek
  • Ministry of Education, India
  • Vlaamse regering
  • National Institutes of Health (DGE1144152, GM061354)
  • Fundação para a Ciência e a Tecnologia (HMSP-ICT/0016/2013)
  • National Institute of Mental Health (F32MH110124, R00MH095867, K99MH095867)
  • National Institute of General Medical Sciences (P01GM061354)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD085857, R01HD081256)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
congenital malformations, whole genome sequencing, topologically associating domains, gene disruption, MEF2C, chromosome topology, gene expression regulation, clinical outcome prediction
MeSH terms
Congenital Abnormalities, Chromosome Aberrations, Female, Genetic Markers, Humans, Male, Gene Rearrangement, Genetic Predisposition to Disease, Genome-Wide Association Study

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