Title

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

Authors

Dong Li, The Children's Hospital of Philadelphia
Michael E. March, The Children's Hospital of Philadelphia
Paola Fortugno, IRCCS Istituto Dermopatico dell'Immacolata
Liza L. Cox, UMKC School of Dentistry
Leticia S. Matsuoka, The Children's Hospital of Philadelphia
Rosanna Monetta, IRCCS Istituto Dermopatico dell'Immacolata
Christoph Seiler, The Children's Hospital of Philadelphia
Louise C. Pyle, The Children's Hospital of Philadelphia
Emma C. Bedoukian, The Children's Hospital of Philadelphia
María José Sánchez-Soler, Hospital Clínico Universitario Virgen de la Arrixaca
Oana Caluseriu, University of Alberta, Faculty of Medicine and Dentistry
Katheryn Grand, Cedars-Sinai Medical Center
Allison Tam, University of California, San Francisco
Alicia R.P. Aycinena, University of California, San Francisco
Letizia Camerota, Università degli Studi dell'Aquila
Yiran Guo, The Children's Hospital of Philadelphia
Patrick Sleiman, The Children's Hospital of Philadelphia
Bert Callewaert, Universitair Ziekenhuis Gent
Candy Kumps, Universitair Ziekenhuis Gent
Annelies Dheedene, Universitair Ziekenhuis Gent
Michael Buckley, Prince of Wales Hospital
Edwin P. Kirk, Prince of Wales Hospital
Anne Turner, Sydney Children's Hospital, Randwick
Benjamin Kamien, King Edward Memorial Hospital for Women
Chirag Patel, Royal Brisbane and Women's Hospital
Meredith Wilson, The Children's Hospital at Westmead
Tony Roscioli, Prince of Wales Hospital
John Christodoulou, Murdoch Children's Research Institute
Timothy C. Cox, UMKC School of Dentistry
Elaine H. Zackai, University of Pennsylvania Perelman School of Medicine
Francesco Brancati, Università degli Studi dell'Aquila
Hakon Hakonarson, The Children's Hospital of Philadelphia

Document Type

Journal Article

Publication Date

7-1-2021

Journal

Human Genetics

Volume

140

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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