Browsing by Author "Redin, Claire"
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- Genomic landscape of balanced cytogenetic abnormalities in subjects with multiple congenital anomaliesPublication . Redin, Claire; Brand, Harrison; Collins, Ryan; Hanscom, Carrie; Vamsee, Pillalamarri; Kammin, Tammy; Mitchell, E.; Hodge, J.C.; Schilit, S.; Curall, B.B.; Pereira, S.; Seabra, C.; Stone, M.; Lawless, W.; Lucente, D.; Antolik, C.; Hochstenbach, R.; Renkens, I.; Brilstra, E.; Vergult, S.; Menten, B.; Janssens, S.; Callewaert, B.; D’heedene, A.; D’hooghe, M; Roelens, F.; van de Kamp, J.; Nieuwint, A.; Poddighe, P.J; van Ravenswaaij-Arts, C.; Rump, P.; van Essen, T.; Freixo, J.; David, Dezső; Liao, E.C.; Leew, N. de; Brunner, H.G.; Kloosterman, W.; Thorland, E.C.; Morton, C.C.; Gusella, J.F.; Talkowski, M E.Balanced chromosomal abnormalities (BCAs) represent a unique class of genomic variation that involves large rearrangement of the chromosomes. To date their detection has been limited to cytogenetic resolution as most first-tier genetic screening methods are blind to their presence. We defined the genomic landscape of de novo BCAs associated with human congenial anomalies in 235 subjects using whole-genome sequencing. We observed that 22% of all BCAs harbored additional cryptic complexity, ranging from three breakpoints to chromothripsis events involving up to 57 breakpoints. Compared to random expectations, BCAs were more likely to occur between loci in close physical proximity in the nucleus, and their breakpoints were significantly enriched for evolutionarily constrained and embryonically expressed genes. From our convergent genomic interpretation using orthogonal datasets, we predict that the congenital anomaly phenotype was likely attributable to the BCA in at least 30% of subjects. An additional 4% of BCAs disrupted long-range regulatory regions such as topologically associating domains (TADs) resulting in position effects on genes associated with specific clinical manifestations that were compatible with the proband sequenced here. Remarkably, we observed a cluster of six independent translocations that disrupted a TAD and consequently altered MEF2C expression, mimicking the 5q14.3 microdeletion syndrome. These results suggest that de novo BCAs represent a highly penetrant class of genomic variation associated with congenital anomalies, and that nucleotide resolution offers insights into phenotypic prediction from direct gene disruption and alteration of long-range regulatory domains that are likely to be a significant source of causal variation in human disease.
- The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomaliesPublication . Redin, Claire; Brand, Harrison; Collins, Ryan L.; Kammin, Tammy; Mitchell, Elyse; Hodge, Jennelle C.; Hanscom, Carrie; Pillalamarri, Vamsee; Seabra, Catarina M.; Abbott, Mary-Alice; Abdul-Rahman, Omar A.; de Vries, Bert B A.; Earl, Dawn L.; Ferguson, Heather L.; Harris, David J.; Fisher, Heather; FitzPatrick, David R.; Gerrol, Pamela; Giachino, Daniela; Glessner, Joseph T.; Gliem, Troy; Margolin, Lauren; Grady, Margo; Graham, Brett H.; Griffis, Cristin; Hayden, Mark A.; Hill, Rosamund; Hochstenbach, Ron; Hoffman, Jodi D.; Hopkin, Robert J.; Hubshman, Monika W.; Moya, Graciela; Mason, Tamara; Innes, A Micheil; Irons, Mira; Irving, Melita; Jacobsen, Jessie C.; Janssens, Sandra; Jewett, Tamison; Johnson, John P.; Jongmans, Marjolijn C.; Kahler, Stephen G.; Koolen, David A.; Masser-Frye, Diane; Nieuwint, Aggie W.; Korzelius, Jerome; Kroisel, Peter M.; Lacassie, Yves; Lawless, William; Lemyre, Emmanuelle; Leppig, Kathleen; Levin, Alex V.; Li, Haibo; Li, Hong; Parkash, Sandhya; Liao, Eric C.; Ordulu, Zehra; Lim, Cynthia; Lose, Edward J.; Lucente, Diane; Macera, Michael J.; Manavalan, Poornima; Mandrile, Giorgia; Marcelis, Carlo L.; McClellan, Michael W.; Mendoza, Cinthya J. Zepeda; Menten, Björn; Middelkamp, Sjors; Mikami, Liya R.; Moe, Emily; Wiley, Susan; Mohammed, Shehla; Mononen, Tarja; Mortenson, Megan E.; Pauker, Susan P.; Pereira, Shahrin; Perrin, Danielle; Phelan, Katy; Aguilar, Raul E Piña; Poddighe, Pino J.; Aberg, Erika; Wilson, Anna; Pregno, Giulia; Raskin, Salmo; Reis, Linda; Rhead, William; Rita, Debra; Renkens, Ivo; Roelens, Filip; Ruliera, Jayla; Rump, Patrick; Schilit, Samantha L.P.; Yerena-de Vega, Maria de la Concepcion A.; Adley, Rhett; Shaheen, Ranad; Sparkes, Rebecca; Spiegel, Erica; Stevens, Blair; Stone, Matthew R.; Tagoe, Julia; Thakuria, Joseph V.; van Bon, Bregje W.; van de Kamp, Jiddeke; Alkuraya, Fowzan S.; van Der Burgt, Ineke; Alcaraz-Estrada, Sofia L.; van Essen, Ton; van Ravenswaaij-Arts, Conny M.; van Roosmalen, Markus J.; Vergult, Sarah; Volker-Touw, Catharina M.L.; Warburton, Dorothy P.; Waterman, Matthew J.; Zori, Roberto T.; Levy, Brynn; Brunner, Han G.; de Leeuw, Nicole; Kloosterman, Wigard P.; Thorland, Erik C.; Gripp, Karen W.; Morton, Cynthia C.; Gusella, James F.; Talkowski, Michael E.; An, Yu; Anderson, Mary-Anne; Antolik, Caroline; Anyane-Yeboa, Kwame; Atkin, Joan F.; Bartell, Tina; Bernstein, Jonathan A.; Gropman, Andrea L.; Beyer, Elizabeth; Blumenthal, Ian; Bongers, Ernie M.H.F.; Brilstra, Eva H.; Brown, Chester W.; Brüggenwirth, Hennie T.; Callewaert, Bert; Chiang, Colby; Corning, Ken; Cox, Helen; Hanson-Kahn, Andrea; Cuppen, Edwin; Currall, Benjamin B.; Cushing, Tom; David, Dezső; Deardorff, Matthew A.; Dheedene, Annelies; D'Hooghe, MarcDespite 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.