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Cornelia de Lange syndrome in diverse populations

Dowsett L 1 , Porras AR 2 , Kruszka P 3 , Davis B 3 , Hu T 3 , Honey E 4 Show all authors , Badoe E 5 , Thong MK 6 , Leon E 7 , Girisha KM 8 , Shukla A 8 , Nayak SS 8 , Shotelersuk V 9 , Megarbane A 10 , Phadke S 11 , Sirisena ND 12 , Dissanayake VHW 12 , Ferreira CR 7 , Kisling MS 7 , Tanpaiboon P 7 , Uwineza A 13 , Mutesa L 13 , Tekendo-Ngongang C 14 , Wonkam A 14 , Fieggen K 14 , Batista LC 15 , Moretti-Ferreira D 15 , Stevenson RE 16 , Prijoles EJ 16 , Everman D 16 , Clarkson K 16 , Worthington J 16 , Kimonis V 17 , Hisama F 18 , Crowe C 19 , Wong P 20 , Johnson K 20 , Clark RD 21 , Bird L 22 , Masser-Frye D 23 , McDonald M 24 , Willems P 25 , Roeder E 26 , Saitta S 27 , Anyane-Yeoba K 28 , Demmer L 29 , Hamajima N 30 , Stark Z 31 , Gillies G 32 , Hudgins L 33 , Dave U 34 , Shalev S 35 , Siu V 36 , Ades A 37 , Dubbs H 38 , Raible S 1 , Kaur M 1 , Salzano E 1 , Jackson L 1 , Deardorff M 1 , Kline A 39 , Summar M 7 , Muenke M 3 , Linguraru MG 2 , Krantz ID 1

Affiliations 

  • 1 Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 2 Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Health System, Washington, District of Columbia
  • 3 Medical Genetics Branch, National Human Genome Research Institute, The National Institutes of Health, Bethesda, Maryland
  • 4 Department of Genetics, University of Pretoria, Pretoria, South Africa
  • 5 School of Medicine and Dentistry, College of Health Sciences, University of Ghana, Accra, Ghana
  • 6 Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 7 Division of Genetics and Metabolism, Children's National Health System, Washington, District of Columbia
  • 8 Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
  • 9 Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  • 10 Research Institut, Institut Jérôme Lejeune, Paris, France
  • 11 Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
  • 12 Human Genetics Unit, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
  • 13 Center for Human Genetics, University of Rwanda, College of Medicine and Health Sciences, School of Medicine and Pharmacy, Kigali, Rwanda
  • 14 Division of Human Genetics, University of Cape Town, Cape Town, South Africa
  • 15 Department of Genetics, Institute of Biosciences, São Paulo State University-UNESP, São Paulo, Brazil
  • 16 Greenwood Genetic Center, Greenwood, South Carolina
  • 17 Department of Pediatrics, Division of Genetics and Genomic Medicine, University of California, Irvine, California
  • 18 Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington
  • 19 MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
  • 20 Department of Pediatrics, Rush University Medical College, Chicago, Illinois
  • 21 Division of Medical Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California
  • 22 Department of Pediatrics, University of California Sand Diego, San Diego, California
  • 23 Department of Genetics, Rady Children's Hospital, San Diego, California
  • 24 Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, North Carolina
  • 25 GENDIA, GENetic DIAgnostic Network, Antwerp, Belgium
  • 26 Department of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
  • 27 Division of Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, Medical Genetics Institute, Los Angeles, California
  • 28 Division of Clinical Genetics, Columbia University Medical College, New York, New York
  • 29 Department of Pediatrics, Carolinas Medical Center, Charlotte, North Carolina
  • 30 Department of Pediatrics, Nagoya City Jouhoku Hospital, Nagoya, Japan
  • 31 Murdoch Children's Research Institute, Victorian Clinical Genetics Services, Melbourne, Australia
  • 32 Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Melbourne, Australia
  • 33 Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Palo Alto, California
  • 34 Haffkine Institute, MILS International India, Mumbai, India
  • 35 Ha'emek Medical Center, The Genetic Institute, Hafia, Israel
  • 36 Medical Genetics Program, London Health Sciences Centre, Ontario, Canada
  • 37 The Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
  • 38 Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 39 Department of Pediatrics, Greater Baltimore Medical Center, Harvey Institute for Human Genetics, Baltimore, Maryland
Am J Med Genet A, 2019 02;179(2):150-158.
PMID: 30614194 DOI: 10.1002/ajmg.a.61033

Abstract

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.

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

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