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

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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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Data availability

The variants are available in the Leiden Open Variation Database (LOVD, www.LOVD.nl/CDH11).

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Acknowledgements

We thank all the families involved in this study for their participation.

Funding

Research reported in this publication was supported in part by the Roberts Collaborative Functional Genomics Rapid Grant (to D.L., C.S., L.P.) from CHOP. The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program. F.B. acknowledges for support and is member of the Italian Undiagnosed Rare Diseases Network led by Dr. Domenica Taruscio (Director, National Centre for Rare Diseases, Istituto Superiore Sanità, Italy). We would like to thank Prof. Ian Glass and Mei Deng, Birth Defects Research Laboratory, University of Washington, for conceptual tissues.

Author information

Author notes

  1. Dong Li and Michael E. March contributed equally to this work.

Authors and Affiliations

  1. Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Dong Li, Michael E. March, Leticia S. Matsuoka, Yiran Guo, Patrick Sleiman, Hakon Hakonarson & Elizabeth J. Bhoj

  2. Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome, Italy

    Paola Fortugno & Rosanna Monetta

  3. Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy

    Paola Fortugno, Rosanna Monetta, Letizia Camerota & Francesco Brancati

  4. Departments of Oral and Craniofacial Sciences and Pediatrics, University of Missouri-Kansas City School of Dentistry, Kansas City, MO, 64108, USA

    Liza L. Cox & Timothy C. Cox

  5. Zebrafish Core Facility, The Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA, USA

    Christoph Seiler

  6. Individualized Medical Genetics Center, Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Louise C. Pyle & Emma C. Bedoukian

  7. Sección de Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, España

    María José Sánchez-Soler

  8. Department of Medical Genetics, University of Alberta, Edmonton, AB, T6G 2H7, Canada

    Oana Caluseriu

  9. The Stollery Pediatric Hospital, Edmonton, AB, T6G 2H7, Canada

    Oana Caluseriu

  10. Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Katheryn Grand

  11. Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA

    Allison Tam & Alicia R. P. Aycinena

  12. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Patrick Sleiman, Elaine H. Zackai, Hakon Hakonarson & Elizabeth J. Bhoj

  13. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

    Bert Callewaert, Candy Kumps & Annelies Dheedene

  14. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

    Bert Callewaert

  15. NSW Health Pathology Genomics Laboratory, Prince of Wales Hospital, Randwick, NSW, Australia

    Michael Buckley, Edwin P. Kirk & Tony Roscioli

  16. Centre for Clinical Genetics, Sydney Children’s Hospital, Randwick, NSW, Australia

    Edwin P. Kirk, Anne Turner & Tony Roscioli

  17. Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia

    Benjamin Kamien

  18. Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    Chirag Patel

  19. Department of Clinical Genetics, Children’s Hospital at Westmead, Sydney, NSW, Australia

    Meredith Wilson

  20. Neuroscience Research Australia and Prince of Wales Clinical School, University of New South Wales, Kensington, NSW, Australia

    Tony Roscioli

  21. Murdoch Children’s Research Institute, Melbourne, Australia

    John Christodoulou

  22. Department of Paediatrics, University of Melbourne, Melbourne, Australia

    John Christodoulou

  23. Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, Australia

    John Christodoulou

  24. Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Elaine H. Zackai, Hakon Hakonarson & Elizabeth J. Bhoj

  25. Institute of Translational Pharmacology, National Research Council, Rome, Italy

    Francesco Brancati

  26. IRCCS San Raffaele Pisana, Rome, Italy

    Francesco Brancati

Authors
  1. Dong Li
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  2. Michael E. March
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  3. Paola Fortugno
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  6. Rosanna Monetta
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  7. Christoph Seiler
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  8. Louise C. Pyle
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  9. Emma C. Bedoukian
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  10. María José Sánchez-Soler
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  11. Oana Caluseriu
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  12. Katheryn Grand
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  13. Allison Tam
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  14. Alicia R. P. Aycinena
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  15. Letizia Camerota
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  16. Yiran Guo
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  17. Patrick Sleiman
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  18. Bert Callewaert
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  19. Candy Kumps
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  20. Annelies Dheedene
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  21. Michael Buckley
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  22. Edwin P. Kirk
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  23. Anne Turner
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  24. Benjamin Kamien
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  25. Chirag Patel
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  26. Meredith Wilson
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  27. Tony Roscioli
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  28. John Christodoulou
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  29. Timothy C. Cox
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  30. Elaine H. Zackai
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  31. Francesco Brancati
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  32. Hakon Hakonarson
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  33. Elizabeth J. Bhoj
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Contributions

DL, MB, EPK, TCC, and HH contributed to the molecular evaluation of the affected individuals. LCP, ECB, MSS, OC, KG, AT, APA, LC, BC, CK, AT, BK, CP, MW, TR, EHZ, and EJB contributed to the clinical evaluation of the affected individuals. DL, MEM, PF, LLC, LSM, RM, CS, and FR contributed to the functional investigations. YG, PS, AD, and JC coordinated to the research study subject enrollment. All the authors read, edited, and approved the manuscript.

Corresponding authors

Correspondence to Dong Li or Elizabeth J. Bhoj.

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None of the authors has any conflicts of interests to declare.

Consent to participate and publish

All the patients’ families from the different institutions agreed to participate and publish in this study and signed appropriate consent forms. The Institutional Review Board of The Children’s Hospital of Philadelphia approved this study. We obtained photo consent for including patients’ photographs from The Children’s Hospital of Philadelphia, Hospital Clínico Universitario Virgen de la Arrixaca, Ghent University Hospital, and Sydney Children’s Hospital.

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Li, D., March, M.E., Fortugno, P. et al. Pathogenic variants in CDH11 impair cell adhesion and cause Teebi hypertelorism syndrome. Hum Genet 140, 1061–1076 (2021). https://doi.org/10.1007/s00439-021-02274-3

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