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

(2017) NATURE GENETICS. 49(1). p.36-45
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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.
Keywords
AUTISM SPECTRUM DISORDER, DE-NOVO MUTATIONS, SEVERE MENTAL-RETARDATION, OF-FUNCTION MUTATIONS, MICRODELETION SYNDROME, CHROMOSOME, REARRANGEMENTS, INTELLECTUAL DISABILITY, STRUCTURAL VARIATION, DEVELOPMENTAL DELAY, CANCER GENOMES

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Chicago
Redin, Claire, Harrison Brand, Ryan L Collins, Tammy Kammin, Elyse Mitchell, Jennelle C Hodge, Carrie Hanscom, et al. 2017. “The Genomic Landscape of Balanced Cytogenetic Abnormalities Associated with Human Congenital Anomalies.” Nature Genetics 49 (1): 36–45.
APA
Redin, C., Brand, H., Collins, R. L., Kammin, T., Mitchell, E., Hodge, J. C., Hanscom, C., et al. (2017). The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. NATURE GENETICS, 49(1), 36–45.
Vancouver
1.
Redin C, Brand H, Collins RL, Kammin T, Mitchell E, Hodge JC, et al. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. NATURE GENETICS. 2017;49(1):36–45.
MLA
Redin, Claire, Harrison Brand, Ryan L Collins, et al. “The Genomic Landscape of Balanced Cytogenetic Abnormalities Associated with Human Congenital Anomalies.” NATURE GENETICS 49.1 (2017): 36–45. Print.
@article{8513622,
  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.},
  author       = {Redin, Claire and Brand, Harrison and Collins, Ryan L and Kammin, Tammy and Mitchell, Elyse and Hodge, Jennelle C and Hanscom, Carrie and Pillalamarri, Vamsee and Seabra, Catarina M and Abbott, Mary-Alice and Abdul-Rahman, Omar A and Aberg, Erika and Adley, Rhett and Alcaraz-Estrada, Sofia L and Alkuraya, Fowzan S and An, Yu and Anderson, Mary-Anne and Antolik, Caroline and Anyane-Yeboa, Kwame and Atkin, Joan F and Bartell, Tina and Bernstein, Jonathan A and Beyer, Elizabeth and Blumenthal, Ian and Bongers, Ernie MHF and Brilstra, Eva H and Brown, Chester W and Bruggenwirth, Hennie T and Callewaert, Bert and Chiang, Colby and Corning, Ken and Cox, Helen and Cuppen, Edwin and Currall, Benjamin B and Cushing, Tom and David, Dezso and Deardorff, Matthew A and Dheedene, Annelies and D'Hooghe, Marc and de Vries, Bert BA and Earl, Dawn L and Ferguson, Heather L and Fisher, Heather and FitzPatrick, David R and Gerrol, Pamela and Giachino, Daniela and Glessner, Joseph T. and Gliem, Troy and Grady, Margo and Graham, Brett H and Griffis, Cristin and Gripp, Karen W and Gropman, Andrea L and Hanson-Kahn, Andrea and Harris, David J and Hayden, Mark A and Hill, Rosamund and Hochstenbach, Ron and Hoffman, Jodi D and Hopkin, Robert J and Hubshman, Monika W and Innes, A Micheil and Irons, Mira and Irving, Melita and Jacobsen, Jessie C and Janssens, Sandra and Jewett, Tamison and Johnson, John P and Jongmans, Marjolijn C and Kahler, Stephen G and Koolen, David A and Korzelius, Jerome and Kroisel, Peter M and Lacassie, Yves and Lawless, William and Lemyre, Emmanuelle and Leppig, Kathleen and Levin, Alex V and Li, Haibo and Li, Hong and Liao, Eric C and Lim, Cynthia and Lose, Edward J and Lucente, Diane and Macera, Michael J and Manavalan, Poornima and Mandrile, Giorgia and Marcelis, Carlo L and Margolin, Lauren and Mason, Tamara and Masser-Frye, Diane and McClellan, Michael W and Zepeda Mendoza, Cinthya J and Menten, Bj{\"o}rn and Middelkamp, Sjors and Mikami, Liya R and Moe, Emily and Mohammed, Shehla and Mononen, Tarja and Mortenson, Megan E and Moya, Graciela and Nieuwint, Aggie W and Ordulu, Zehra and Parkash, Sandhya and Pauker, Susan P and Pereira, Shahrin and Perrin, Danielle and Phelan, Katy and Pina Aguilar, Raul E and Poddighe, Pino J and Pregno, Giulia and Raskin, Salmo and Reis, Linda and Rhead, William and Rita, Debra and Renkens, Ivo and Roelens, Filip and Ruliera, Jayla and Rump, Patrick and Schilit, Samantha LP and Shaheen, Ranad and Sparkes, Rebecca and Spiegel, Erica and Stevens, Blair and Stone, Matthew R and Tagoe, Julia and Thakuria, Joseph V and van Bon, Bregje W and van de Kamp, Jiddeke and van Der Burgt, Ineke and van Essen, Ton and van Ravenswaaij-Arts, Conny M and van Roosmalen, Markus J and Vergult, Sarah and Volker-Touw, Catharina ML and Warburton, Dorothy P and Waterman, Matthew J and Wiley, Susan and Wilson, Anna and Yerena-de Vega, Maria de la Concepcion A. and Zori, Roberto T and Levy, Brynn and Brunner, Han G and de Leeuw, Nicole and Kloosterman, Wigard P and Thorland, Erik C and Morton, Cynthia C and Gusella, James F and Talkowski, Michael E},
  issn         = {1061-4036},
  journal      = {NATURE GENETICS},
  keyword      = {AUTISM SPECTRUM DISORDER,DE-NOVO MUTATIONS,SEVERE MENTAL-RETARDATION,OF-FUNCTION MUTATIONS,MICRODELETION SYNDROME,CHROMOSOME,REARRANGEMENTS,INTELLECTUAL DISABILITY,STRUCTURAL VARIATION,DEVELOPMENTAL DELAY,CANCER GENOMES},
  language     = {eng},
  number       = {1},
  pages        = {36--45},
  title        = {The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies},
  url          = {http://dx.doi.org/10.1038/ng.3720},
  volume       = {49},
  year         = {2017},
}

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