Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms

Kaur M 1 , Blair J 1 , Devkota B 2 , Fortunato S 1 , Clark D 3 , Lawrence A 1 Show all authors , Kim J 1 , Do W 1 , Semeo B 1 , Katz O 1 , Mehta D 1 , Yamamoto N 4 , Schindler E 1 , Al Rawi Z 1 , Wallace N 1 , Wilde JJ 5 , McCallum J 6 , Liu J 7 , Xu D 8 , Jackson M 1 , Rentas S 9 , Tayoun AA 10 , Zhe Z 11 , Abdul-Rahman O 12 , Allen B 13 , Angula MA 14 , Anyane-Yeboa K 15 , Argente J 16 , Arn PH 17 , Armstrong L 18 , Basel-Salmon L 19 , Baynam G 20 , Bird LM 21 , Bruegger D 22 , Ch'ng GS 23 , Chitayat D 24 , Clark R 25 , Cox GF 26 , Dave U 27 , DeBaere E 28 , Field M 29 , Graham JM 30 , Gripp KW 31 , Greenstein R 32 , Gupta N 33 , Heidenreich R 34 , Hoffman J 35 , Hopkin RJ 36 , Jones KL 37 , Jones MC 21 , Kariminejad A 38 , Kogan J 39 , Lace B 40 , Leroy J 28 , Lynch SA 41 , McDonald M 42 , Meagher K 18 , Mendelsohn N 43 , Micule I 40 , Moeschler J 44 , Nampoothiri S 45 , Ohashi K 46 , Powell CM 47 , Ramanathan S 25 , Raskin S 48 , Roeder E 49 , Rio M 50 , Rope AF 51 , Sangha K 18 , Scheuerle AE 52 , Schneider A 53 , Shalev S 54 , Siu V 55 , Smith R 56 , Stevens C 57 , Tkemaladze T 58 , Toimie J 59 , Toriello H 60 , Turner A 61 , Wheeler PG 62 , White SM 63 , Young T 64 , Loomes KM 65 , Pipan M 66 , Harrington AT 67 , Zackai E 1 , Rajagopalan R 68 , Conlin L 68 , Deardorff MA 69 , McEldrew D 1 , Pie J 70 , Ramos F 71 , Musio A 72 , Kline AD 73 , Izumi K 1 , Raible SE 1 , Krantz ID 1

Affiliations 

  • 1 Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  • 2 Illumina Inc, San Diego, California, USA
  • 3 Natera, Inc., Austin, Texas, USA
  • 4 Division of Otolaryngology, National Center for Child Health and Development, Tokyo, Japan
  • 5 Emugen Therapeutics, Woburn, Massachusetts, USA
  • 6 Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  • 7 Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
  • 8 Hematologics Inc, Seattle, Washington, USA
  • 9 Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA
  • 10 Al Jalila Genomics Center, Al Jalila Children's Hospital, Dubai, United Arab Emirates
  • 11 Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  • 12 Department of Genetic Medicine, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA
  • 13 Fullerton Genetics Center, Mission Health, Asheville, North Carolina, USA
  • 14 Department of Pediatrics, NYU Langone Hospital-Long Island, Mineola, New York, USA
  • 15 Pediatrics, Columbia University Irving Medical Center, New York, New York, USA
  • 16 Hospital Infantil Universitario Niño Jesús & Universidad Autónoma de Madrid, Madrid, Spain
  • 17 Department of Pediatrics, Nemours Children's Specialty Care, Jacksonville, Florida, USA
  • 18 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
  • 19 Rabin Medical Center-Beilinson Hospital, Raphael Recanati Genetics Institute, Petach Tikva, Israel
  • 20 Western Australian Register of Developmental Anomalies and Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia
  • 21 Department of Pediatrics, University of California San Diego, San Diego, California, USA
  • 22 Department of Otolaryngology-Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas, USA
  • 23 Department of Genetics, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia
  • 24 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
  • 25 Department of Pediatrics, Division of Medical Genetics, Loma Linda University School of Medicine, Loma Linda, California, USA
  • 26 Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  • 27 R & D MILS International India, Mumbai, India
  • 28 Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
  • 29 Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia
  • 30 Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA
  • 31 Nemours Children's Health, Wilmington, Delaware, USA
  • 32 University of Connecticut Health Center, Farmington, Connecticut, USA
  • 33 Division of Genetics, Department of Paediatrics, All India Institute of Medical Sciences, New Delhi, India
  • 34 Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
  • 35 Department of Pediatrics, Boston University School of Medicine, Boston, Massachusetts, USA
  • 36 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  • 37 Division of Dysmorphology & Teratology, Department of Pediatrics, University of California San Diego School of Medicine, San Diego, California, USA
  • 38 Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran
  • 39 Division of Genetics, Advocate Children's Hospital, Park Ridge, Illinois, USA
  • 40 Children's Clinical University Hospital, Riga, Latvia
  • 41 Department of Clinical Genetics, Children's Health Ireland, Dublin, Ireland
  • 42 Duke University Medical Center, Durham, North Carolina, USA
  • 43 Complex Health Solutions, United Healthcare, Minneapolis, Minnesota, USA
  • 44 Department of Pediatrics, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA
  • 45 Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Cochin, India
  • 46 Department of Medical Genetics, BC Women's Hospital, Vancouver, British Columbia, Canada
  • 47 Division of Genetics and Metabolism, Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
  • 48 Genetika-Centro de aconselhamento e laboratório de genética, Curitiba, Brazil
  • 49 Department of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, Texas, USA
  • 50 Department of Genetics, Hôpital Necker-Enfants Malades, Paris, France
  • 51 Genome Medical, South San Francisco, California, USA
  • 52 Division of Genetics and Metabolism, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  • 53 Department of Pediatrics and Oculogenetics, Wills Eye Hospital, Philadelphia, Pennsylvania, USA
  • 54 Rappaport Faculty of Medicine, Technion, The Genetics Institute, Emek Medical Center, Afula, Haifa, Israel
  • 55 London Health Sciences Centre, London, Ontario, Canada
  • 56 Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, Maine, USA
  • 57 Department of Pediatrics, University of Tennessee College of Medicine, T.C. Thompson Children's Hospital, Chattanooga, Tennessee, USA
  • 58 Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi, Georgia
  • 59 Clinical Genetics Service, Laboratory Medicine Building, Southern General Hospital, Glasgow, UK
  • 60 Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan, USA
  • 61 Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, New South Wales, Australia
  • 62 Division of Genetics, Arnold Palmer Hospital, Orlando, Florida, USA
  • 63 Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Australia
  • 64 Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
  • 65 Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  • 66 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  • 67 Center for Rehabilitation, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  • 68 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  • 69 Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
  • 70 Laboratorio de Genética Clínica y Genómica Funcional, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain
  • 71 Unidad de Genética Clínica, Servicio de Pediatría, Hospital Clínico Universitario "Lozano Blesa", Zaragoza, Spain
  • 72 Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, Pisa
  • 73 Greater Baltimore Medical Centre, Harvey Institute of Human Genetics, Baltimore, Maryland, USA
Am J Med Genet A, 2023 Aug;191(8):2113-2131.
PMID: 37377026 DOI: 10.1002/ajmg.a.63247

Abstract

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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