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

doi:10.1038/ng.3720

. 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

Claire Redin^{1

2

3}, Harrison Brand^{1

2

3}, Ryan L Collins^{1

2

3

4}, Tammy Kammin⁵, Elyse Mitchell⁶, Jennelle C Hodge^{6

7

8}, Carrie Hanscom^{1

2

3}, Vamsee Pillalamarri^{1

2

3}, Catarina M Seabra^{1

2

3

9}, Mary-Alice Abbott¹⁰, Omar A Abdul-Rahman¹¹, Erika Aberg¹², Rhett Adley¹, Sofia L Alcaraz-Estrada¹³, Fowzan S Alkuraya¹⁴, Yu An^{1

15}, Mary-Anne Anderson¹⁶, Caroline Antolik^{1

2

3}, Kwame Anyane-Yeboa¹⁷, Joan F Atkin^{18

19}, Tina Bartell²⁰, Jonathan A Bernstein²¹, Elizabeth Beyer^{22

23}, Ian Blumenthal¹, Ernie M H F Bongers²⁴, Eva H Brilstra²⁵, Chester W Brown^{26

27}, Hennie T Brüggenwirth²⁸, Bert Callewaert²⁹, Colby Chiang¹, Ken Corning³⁰, Helen Cox³¹, Edwin Cuppen²⁵, Benjamin B Currall^{1

5

32}, Tom Cushing³³, Dezso David³⁴, Matthew A Deardorff^{35

36}, Annelies Dheedene²⁹, Marc D'Hooghe³⁷, Bert B A de Vries²⁴, Dawn L Earl³⁸, Heather L Ferguson⁵, Heather Fisher³⁹, David R FitzPatrick⁴⁰, Pamela Gerrol⁵, Daniela Giachino⁴¹, Joseph T Glessner^{1

2

3}, Troy Gliem⁶, Margo Grady⁴², Brett H Graham^{26

27}, Cristin Griffis^{22

23}, Karen W Gripp⁴³, Andrea L Gropman⁴⁴, Andrea Hanson-Kahn^{21

45}, David J Harris^{46

47}, Mark A Hayden⁵, Rosamund Hill⁴⁸, Ron Hochstenbach²⁵, Jodi D Hoffman⁴⁹, Robert J Hopkin^{50

51}, Monika W Hubshman^{52

53

54}, A Micheil Innes⁵⁵, Mira Irons⁵⁶, Melita Irving^{57

58}, Jessie C Jacobsen⁵⁹, Sandra Janssens²⁹, Tamison Jewett⁶⁰, John P Johnson⁶¹, Marjolijn C Jongmans²⁴, Stephen G Kahler⁶², David A Koolen²⁴, Jerome Korzelius²⁵, Peter M Kroisel⁶³, Yves Lacassie⁶⁴, William Lawless¹, Emmanuelle Lemyre⁶⁵, Kathleen Leppig^{66

67}, Alex V Levin⁶⁸, Haibo Li⁶⁹, Hong Li⁶⁹, Eric C Liao^{70

71

72}, Cynthia Lim^{62

73}, Edward J Lose⁷⁴, Diane Lucente¹, Michael J Macera⁷⁵, Poornima Manavalan¹, Giorgia Mandrile⁴¹, Carlo L Marcelis²⁴, Lauren Margolin⁷⁶, Tamara Mason⁷⁶, Diane Masser-Frye⁷⁷, Michael W McClellan⁷⁸, Cinthya J Zepeda Mendoza^{5

79}, Björn Menten²⁹, Sjors Middelkamp²⁵, Liya R Mikami^{80

81}, Emily Moe^{22

23}, Shehla Mohammed⁵⁷, Tarja Mononen⁸², Megan E Mortenson^{60

83}, Graciela Moya⁸⁴, Aggie W Nieuwint⁸⁵, Zehra Ordulu^{5

79}, Sandhya Parkash^{12

86}, Susan P Pauker^{79

87}, Shahrin Pereira⁵, Danielle Perrin⁷⁶, Katy Phelan⁸⁸, Raul E Piña Aguilar^{13

89}, Pino J Poddighe⁸⁵, Giulia Pregno⁴¹, Salmo Raskin⁸⁰, Linda Reis^{22

90}, William Rhead^{22

23

91}, Debra Rita⁹², Ivo Renkens²⁵, Filip Roelens⁹³, Jayla Ruliera¹⁶, Patrick Rump⁹⁴, Samantha L P Schilit^{32

79}, Ranad Shaheen¹⁴, Rebecca Sparkes⁵⁵, Erica Spiegel⁹⁵, Blair Stevens⁹⁶, Matthew R Stone^{1

2

3}, Julia Tagoe⁹⁷, Joseph V Thakuria^{79

98}, Bregje W van Bon²⁴, Jiddeke van de Kamp⁸⁵, Ineke van Der Burgt²⁴, Ton van Essen⁹⁴, Conny M van Ravenswaaij-Arts⁹⁴, Markus J van Roosmalen²⁵, Sarah Vergult²⁹, Catharina M L Volker-Touw²⁵, Dorothy P Warburton¹⁷, Matthew J Waterman^{1

99}, Susan Wiley¹⁰⁰, Anna Wilson¹, Maria de la Concepcion A Yerena-de Vega¹⁰¹, Roberto T Zori¹⁰², Brynn Levy¹⁰³, Han G Brunner^{24

104}, Nicole de Leeuw²⁴, Wigard P Kloosterman²⁵, Erik C Thorland⁶, Cynthia C Morton^{3

5

79

105

106}, James F Gusella^{1

3

32}, Michael E Talkowski^{1

2

3}

Affiliations

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.

PMID: 27841880
PMCID: PMC5307971
DOI: 10.1038/ng.3720

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

Claire Redin et al. Nat Genet. 2017 Jan.

. 2017 Jan;49(1):36-45.

doi: 10.1038/ng.3720. Epub 2016 Nov 14.

Authors

Affiliations

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.

PMID: 27841880
PMCID: PMC5307971
DOI: 10.1038/ng.3720

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.

PubMed Disclaimer

Conflict of interest statement

The authors have none to declare.

Figures

**Figure 1**
Characterization of BCAs detected by karyotyping at nucleotide resolution a. Genome-wide map of all BCA breakpoints identified in the cohort by whole-genome sequencing. One color is used per BCA to represent all rearrangement breakpoints in each subject. The scatter plot on the outside ring denotes breakpoint density per 1-Mb bin across the genome, with a blue arrow displaying the largest clustering of breakpoints at 5q14.3; b. Scatter plot summarizing the overall genomic imbalance associated with fully reconstructed BCAs at varying size thresholds. Curves represent the fraction of cases with final genomic imbalances greater than the corresponding size provided. Solid lines denote the final genomic imbalances for all BCAs, and are further delineated by deletions (red) or duplications (blue). The final genomic imbalances among fully mapped BCAs is also split between cases that have been pre-screened by CMA (dashed line) versus cases without CMA data (dotted line); c. Sequence signatures of BCA breakpoints. Histogram representing nucleotide signatures at the junction of 662 Sanger-validated breakpoints: inserted nucleotides, blunt ends, microhomology, or longer stretches of homology.

**Figure 2**
*De novo* BCAs associated with congenital anomalies disrupt functionally relevant loci. a. Boxplots illustrate specific gene-set enrichments at BCA breakpoints in subjects with congenital anomalies. Each boxplot represents the expected distribution (median, first and third quartiles) based on total intersections between 100,000 sets of simulated breakpoints and a particular gene-set. Red diamonds indicate the observed intersection values. Empirical Monte-Carlo *P-values* are indicated; b. Venn diagram showing the detailed overlap of disrupted genes previously associated with three neurodevelopmental phenotypes in amalgamated exome and CNV studies. In black: high-confidence genes (3 or more *de novo* LoF mutations reported), in grey: low-confidence genes (two *de novo* LoF mutations). **c–e**) Diagnostic yields associated with the overall cohort and multiple subgroups of BCAs. c. Diagnostic yield associated with all 248 mapped BCAs from subjects with congenital or developmental anomalies; d. Diagnostic yields partitioned by inheritance status; e. Diagnostic yields associated with BCAs depleted for large pathogenic CNVs thanks to CMA pre-screen compared to BCAs that had not been pre-screened by CMA.

**Figure 3**
Recurrent disruption of long-range regulatory interactions at the 5q14.3 locus. a. Genome-wide distribution of BCA breakpoints in the cohort across each 1-Mb bin. P-values correspond to observed vs. expected cluster sizes after 100,000 Monte Carlo randomizations. Corrected P-values are reported. One cluster, localized to 5q14.3, achieved genome-wide significance (threshold demarcated by red line); b. Hi-C profile and contact domains at the 5q14.3 locus derived from human LCLs. Overlapping Hi-C data suggests that the topology of the *MEF2C*-contact domain is altered in subjects carrying BCAs. Brain-expressed enhancers located in the region, loops involving *MEF2C* (yellow circles) and CTCF binding sites (green: forward, red: reverse) are indicated. Multiple pathogenic mechanisms converge on a similar syndrome: multi-genic deletions that encompass *MEF2C* along with one or both TAD boundaries (n=68)*, MEF2C*-intragenic deletions (n=12) or LoF mutations, deletions that do not encompass *MEF2C* but overlap one TAD boundary (n=13), and BCA breakpoints distal to *MEF2C* (breakpoints from seven subjects reported in this study and three previously reported subjects)^,,.; c. Proposed model of the chromatin folding in the region defining a regulatory unit for *MEF2C*; d. Significantly decreased expression of *MEF2C* was observed in subjects harboring BCAs distal to *MEF2C* compared to controls. *MEF2C*-expression was measured by qRT-PCR, normalized against three endogenous genes and compared to the average *MEF2C*-expression from 16 age-matched controls (two-sided Wilcoxon rank-sum test: DGAP131, DGAP191, DGAP222: P=0.0085, DGAP218: P=0.0160). Individual expression values, median, first and third quartiles are indicated.

**Figure 4**
Correlations between phenotypes and genes disrupted in subjects harboring pathogenic BCAs. For each gene, the phenotypes reported in the corresponding subject were digitalized using HPO. One tile represents the normalized count of HPO terms belonging to each organ category reported in the subject(s). Genes clustered together when sharing similarly affected organs, from which five groups can be delineated: 1- genes associated with multiple nervous system and craniofacial abnormalities (dark blue); 2- genes connected to multiple neurological phenotypes (pink); 3- genes associated with craniofacial abnormalities and a few neurological symptoms (black); 4- genes associated with skeletal and limb abnormalities, and with limited neurological involvement (green); 5- genes without neurological involvement (light blue).

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References

1. Jacobs PA, Melville M, Ratcliffe S, Keay AJ, Syme J. A cytogenetic survey of 11,680 newborn infants. Ann Hum Genet. 1974;37:359–376. - PubMed
1. Nielsen J, Wohlert M. Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet. 1991;87:81–83. - PubMed
1. Ravel C, Berthaut I, Bresson JL, Siffroi JP Genetics Commission of the French Federation of C. Prevalence of chromosomal abnormalities in phenotypically normal and fertile adult males: large-scale survey of over 10,000 sperm donor karyotypes. Hum Reprod. 2006;21:1484–1489. - PubMed
1. Funderburk SJ, Spence MA, Sparkes RS. Mental retardation associated with “balanced” chromosome rearrangements. Am J Hum Genet. 1977;29:136–141. - PMC - PubMed
1. Marshall CR, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82:477–488. - PMC - PubMed

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[1] Jacobs PA, Melville M, Ratcliffe S, Keay AJ, Syme J. A cytogenetic survey of 11,680 newborn infants. Ann Hum Genet. 1974;37:359–376. - PubMed

[2] Jacobs PA, Melville M, Ratcliffe S, Keay AJ, Syme J. A cytogenetic survey of 11,680 newborn infants. Ann Hum Genet. 1974;37:359–376. - PubMed

[3] Nielsen J, Wohlert M. Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet. 1991;87:81–83. - PubMed

[4] Nielsen J, Wohlert M. Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet. 1991;87:81–83. - PubMed

[5] Ravel C, Berthaut I, Bresson JL, Siffroi JP Genetics Commission of the French Federation of C. Prevalence of chromosomal abnormalities in phenotypically normal and fertile adult males: large-scale survey of over 10,000 sperm donor karyotypes. Hum Reprod. 2006;21:1484–1489. - PubMed

[6] Ravel C, Berthaut I, Bresson JL, Siffroi JP Genetics Commission of the French Federation of C. Prevalence of chromosomal abnormalities in phenotypically normal and fertile adult males: large-scale survey of over 10,000 sperm donor karyotypes. Hum Reprod. 2006;21:1484–1489. - PubMed

[7] Funderburk SJ, Spence MA, Sparkes RS. Mental retardation associated with “balanced” chromosome rearrangements. Am J Hum Genet. 1977;29:136–141. - PMC - PubMed

[8] Funderburk SJ, Spence MA, Sparkes RS. Mental retardation associated with “balanced” chromosome rearrangements. Am J Hum Genet. 1977;29:136–141. - PMC - PubMed

[9] Marshall CR, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82:477–488. - PMC - PubMed

[10] Marshall CR, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82:477–488. - PMC - PubMed

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

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

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