2. Academic Validation
  3. Pathogenic variants in CDH11 impair cell adhesion and cause Teebi hypertelorism syndrome

Pathogenic variants in CDH11 impair cell adhesion and cause Teebi hypertelorism syndrome

  • Hum Genet. 2021 Jul;140(7):1061-1076. doi: 10.1007/s00439-021-02274-3.
Dong Li # 1,  Michael E March # 2,  Paola Fortugno 3 4,  Liza L Cox 5,  Leticia S Matsuoka 2,  Rosanna Monetta 3 4,  Christoph Seiler 6,  Louise C Pyle 7,  Emma C Bedoukian 7,  María José Sánchez-Soler 8,  Oana Caluseriu 9 10,  Katheryn Grand 11,  Allison Tam 12,  Alicia R P Aycinena 12,  Letizia Camerota 4,  Yiran Guo 2,  Patrick Sleiman 2 13,  Bert Callewaert 14 15,  Candy Kumps 14,  Annelies Dheedene 14,  Michael Buckley 16,  Edwin P Kirk 16 17,  Anne Turner 17,  Benjamin Kamien 18,  Chirag Patel 19,  Meredith Wilson 20,  Tony Roscioli 16 17 21,  John Christodoulou 22 23 24,  Timothy C Cox 5,  Elaine H Zackai 13 25,  Francesco Brancati 4 26 27,  Hakon Hakonarson 2 13 25,  Elizabeth J Bhoj 28 29 30
Affiliations

Affiliations

  • 1 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].
  • 2 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 3 Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy.
  • 4 Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
  • 5 Departments of Oral and Craniofacial Sciences and Pediatrics, University of Missouri-Kansas City School of Dentistry, Kansas City, MO, 64108, USA.
  • 6 Zebrafish Core Facility, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA.
  • 7 Individualized Medical Genetics Center, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 8 Sección de Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, España.
  • 9 Department of Medical Genetics, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
  • 10 The Stollery Pediatric Hospital, Edmonton, AB, T6G 2H7, Canada.
  • 11 Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 12 Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
  • 13 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 14 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
  • 15 Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • 16 NSW Health Pathology Genomics Laboratory, Prince of Wales Hospital, Randwick, NSW, Australia.
  • 17 Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia.
  • 18 Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia.
  • 19 Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
  • 20 Department of Clinical Genetics, Children's Hospital at Westmead, Sydney, NSW, Australia.
  • 21 Neuroscience Research Australia and Prince of Wales Clinical School, University of New South Wales, Kensington, NSW, Australia.
  • 22 Murdoch Children's Research Institute, Melbourne, Australia.
  • 23 Department of Paediatrics, University of Melbourne, Melbourne, Australia.
  • 24 Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, Australia.
  • 25 Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 26 Institute of Translational Pharmacology, National Research Council, Rome, Italy.
  • 27 IRCCS San Raffaele Pisana, Rome, Italy.
  • 28 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].
  • 29 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 30 Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].
  • # Contributed equally.
PMID: 33811546 DOI: 10.1007/s00439-021-02274-3
Abstract

Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical Cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca2+ binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.

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