Nat Genet. 2017 Jan;49(1):36-45. doi: 10.1038/ng.3720. Epub 2016 Nov 14.

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

Redin C^1,^2,³, Brand H^1,^2,³, Collins RL^1,^2,^3,⁴, Kammin T⁵, Mitchell E⁶, Hodge JC^6,^7,⁸, Hanscom C^1,^2,³, Pillalamarri V^1,^2,³, Seabra CM^1,^2,^3,⁹, Abbott MA¹⁰, Abdul-Rahman OA¹¹, Aberg E¹², Adley R¹, Alcaraz-Estrada SL¹³, Alkuraya FS¹⁴, An Y^1,¹⁵, Anderson MA¹⁶, Antolik C^1,^2,³, Anyane-Yeboa K¹⁷, Atkin JF^18,¹⁹, Bartell T²⁰, Bernstein JA²¹, Beyer E^22,²³, Blumenthal I¹, Bongers EM²⁴, Brilstra EH²⁵, Brown CW^26,²⁷, Brüggenwirth HT²⁸, Callewaert B²⁹, Chiang C¹, Corning K³⁰, Cox H³¹, Cuppen E²⁵, Currall BB^1,^5,³², Cushing T³³, David D³⁴, Deardorff MA^35,³⁶, Dheedene A²⁹, D'Hooghe M³⁷, de Vries BB²⁴, Earl DL³⁸, Ferguson HL⁵, Fisher H³⁹, FitzPatrick DR⁴⁰, Gerrol P⁵, Giachino D⁴¹, Glessner JT^1,^2,³, Gliem T⁶, Grady M⁴², Graham BH^26,²⁷, Griffis C^22,²³, Gripp KW⁴³, Gropman AL⁴⁴, Hanson-Kahn A^21,⁴⁵, Harris DJ^46,⁴⁷, Hayden MA⁵, Hill R⁴⁸, Hochstenbach R²⁵, Hoffman JD⁴⁹, Hopkin RJ^50,⁵¹, Hubshman MW^52,^53,⁵⁴, Innes AM⁵⁵, Irons M⁵⁶, Irving M^57,⁵⁸, Jacobsen JC⁵⁹, Janssens S²⁹, Jewett T⁶⁰, Johnson JP⁶¹, Jongmans MC²⁴, Kahler SG⁶², Koolen DA²⁴, Korzelius J²⁵, Kroisel PM⁶³, Lacassie Y⁶⁴, Lawless W¹, Lemyre E⁶⁵, Leppig K^66,⁶⁷, Levin AV⁶⁸, Li H⁶⁹, Li H⁶⁹, Liao EC^70,^71,⁷², Lim C^62,⁷³, Lose EJ⁷⁴, Lucente D¹, Macera MJ⁷⁵, Manavalan P¹, Mandrile G⁴¹, Marcelis CL²⁴, Margolin L⁷⁶, Mason T⁷⁶, Masser-Frye D⁷⁷, McClellan MW⁷⁸, Mendoza CJ^5,⁷⁹, Menten B²⁹, Middelkamp S²⁵, Mikami LR^80,⁸¹, Moe E^22,²³, Mohammed S⁵⁷, Mononen T⁸², Mortenson ME^60,⁸³, Moya G⁸⁴, Nieuwint AW⁸⁵, Ordulu Z^5,⁷⁹, Parkash S^12,⁸⁶, Pauker SP^79,⁸⁷, Pereira S⁵, Perrin D⁷⁶, Phelan K⁸⁸, Aguilar RE^13,⁸⁹, Poddighe PJ⁸⁵, Pregno G⁴¹, Raskin S⁸⁰, Reis L^22,⁹⁰, Rhead W^22,^23,⁹¹, Rita D⁹², Renkens I²⁵, Roelens F⁹³, Ruliera J¹⁶, Rump P⁹⁴, Schilit SL^32,⁷⁹, Shaheen R¹⁴, Sparkes R⁵⁵, Spiegel E⁹⁵, Stevens B⁹⁶, Stone MR^1,^2,³, Tagoe J⁹⁷, Thakuria JV^79,⁹⁸, van Bon BW²⁴, van de Kamp J⁸⁵, van Der Burgt I²⁴, van Essen T⁹⁴, van Ravenswaaij-Arts CM⁹⁴, van Roosmalen MJ²⁵, Vergult S²⁹, Volker-Touw CM²⁵, Warburton DP¹⁷, Waterman MJ^1,⁹⁹, Wiley S¹⁰⁰, Wilson A¹, Yerena-de Vega MC¹⁰¹, Zori RT¹⁰², Levy B¹⁰³, Brunner HG^24,¹⁰⁴, de Leeuw N²⁴, Kloosterman WP²⁵, Thorland EC⁶, Morton CC^3,^5,^79,^105,¹⁰⁶, Gusella JF^1,^3,³², Talkowski ME^1,^2,³.

Author information

1: Molecular Neurogenetics Unit, Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
2: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
3: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
4: Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
5: Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
6: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
7: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
8: Department of Pediatrics, University of California, Los Angeles, Los Angeles, California, USA.
9: GABBA Program, University of Porto, Porto, Portugal.
10: Medical Genetics, Baystate Medical Center, Springfield, Massachusetts, USA.
11: Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
12: Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada.
13: Medical Genomics Division, Centro Medico Nacional 20 de Noviembre, ISSSTE, Mexico City, Mexico.
14: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
15: Institutes of Biomedical Sciences (IBS) of Shanghai Medical School and MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, China.
16: Center for Human Genetic Research DNA and Tissue Culture Resource, Boston, Massachusetts, USA.
17: Division of Clinical Genetics, Columbia University Medical Center, New York, New York, USA.
18: Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA.
19: Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, Ohio, USA.
20: Department of Genetics, Kaiser Permanente, Sacramento, California, USA.
21: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
22: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
23: Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
24: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
25: Division of Biomedical Genetics, Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
26: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
27: Department of Genetics, Texas Children's Hospital, Houston, Texas, USA.
28: Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, the Netherlands.
29: Center for Medical Genetics, Ghent University, Ghent, Belgium.
30: Greenwood Genetic Center, Columbia, South Carolina, USA.
31: West Midlands Regional Clinical Genetics Unit, Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
32: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
33: Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA.
34: Department of Human Genetics, National Health Institute Doutor Ricardo Jorge, Lisbon, Portugal.
35: Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
36: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
37: Department of Neurology and Child Neurology, Algemeen Ziekenhuis Sint-Jan, Brugge, Belgium.
38: Seattle Children's, Seattle, Washington, USA.
39: Mount Sinai West Hospital, New York, New York, USA.
40: MRC Human Genetics Unit, Institute of Genetic and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
41: Medical Genetics Unit, Department of Clinical and Biological Sciences, University of Torino, Turin, Italy.
42: UW Cancer Center at ProHealth Care, Waukesha, Wisconsin, USA.
43: Sidney Kimmel Medical School at Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
44: Division of Neurogenetics and Developmental Pediatrics, Children's National Medical Center, Washington, DC, USA.
45: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
46: Division of Genetics, Boston Children's Hospital, Boston, Massachusetts, USA.
47: Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
48: Department of Neurology, Auckland City Hospital, Auckland, New Zealand.
49: Division of Genetics, Department of Pediatrics, Boston Medical Center, Boston, Massachusetts, USA.
50: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
51: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
52: Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
53: Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.
54: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
55: Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
56: Academic Affairs, American Board of Medical Specialties, Chicago, Illinois, USA.
57: Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
58: Division of Medical and Molecular Genetics, King's College London, London, UK.
59: Centre for Brain Research and School of Biological Sciences, University of Auckland, Auckland, New Zealand.
60: Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
61: Department of Molecular Genetics, Shodair Children's Hospital, Helena, Montana, USA.
62: Division of Genetics and Metabolism, Arkansas Children's Hospital, Little Rock, Arkansas, USA.
63: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
64: Department of Pediatrics, Louisiana State University Health Sciences Center (LSUHSC) and Children's Hospital, New Orleans, Louisiana, USA.
65: Department of Pediatrics, University of Montreal, CHU Sainte-Justine, Montreal, Quebec, Canada.
66: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
67: Clinical Genetics, Group Health Cooperative, Seattle, Washington, USA.
68: Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
69: Center for Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
70: Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
71: Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
72: Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
73: Virginia G. Piper Cancer Center at HonorHealth, Scottsdale, Arizona, USA.
74: Department of Genetics, University of Alabama at Birmingham (UAB), Birmingham, Alabama, USA.
75: Clinical Cytogenetics Laboratory, New York-Presbyterian Hospital, Columbia University Medical Center, New York, New York, USA.
76: Genomics Platform, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
77: Department of Genetics, Rady Children's Hospital, San Diego, California, USA.
78: Department of Obstetrics and Gynecology, Madigan Army Medical Center, Tacoma, Washington, USA.
79: Harvard Medical School, Boston, Massachusetts, USA.
80: Group for Advanced Molecular Investigation, Graduate Program in Health Sciences, School of Medicine, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil.
81: Centro Universitário Autônomo do Brasil (Unibrasil), Curitiba, Brazil.
82: Department of Clinical Genetics, Kuopio University Hospital, Kuopio, Finland.
83: Novant Health Derrick L. Davis Cancer Center, Winston-Salem, North Carolina, USA.
84: GENOS Laboratory, Buenos Aires, Argentina.
85: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
86: Department of Pediatrics, Maritime Medical Genetics Service, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.
87: Medical Genetics, Harvard Vanguard Medical Associates, Watertown, Massachusetts, USA.
88: Hayward Genetics Program, Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, USA.
89: School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
90: Children's Research Institute, Milwaukee, Wisconsin, USA.
91: Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
92: Midwest Diagnostic Pathology, Aurora Clinical Labs, Rosemont, Illinois, USA.
93: Algemeen Ziekenhuis Delta, Roeselare, Belgium.
94: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
95: Division of Maternal Fetal Medicine, Columbia University Medical Center, New York, New York, USA.
96: McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, Texas, USA.
97: Genetic Services, Alberta Health Services, Lethbridge, Alberta, Canada.
98: Division of Medical Genetics, Massachusetts General Hospital, Boston, Massachusetts, USA.
99: Department of Biology, Eastern Nazarene College, Quincy, Massachusetts, USA.
100: Division of Developmental and Behavioral Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinatti, Ohio, USA.
101: Laboratory of Genetics, Centro Medico Nacional 20 de Noviembre, ISSSTE, Mexico City, Mexico.
102: Division of Pediatric Genetics and Metabolism, University of Florida, Gainesville, Florida, USA.
103: Department of Pathology, Columbia University, New York, New York, USA.
104: Department of Clinical Genetics, and Grow School of Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
105: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
106: Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester Academic Health Science Center, Manchester, UK.

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.