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

Dong Li, Michael E. March, Paola Fortugno, Liza L. Cox, Leticia S. Matsuoka, Rosanna Monetta, Christoph Seiler, Louise C. Pyle, Emma C. Bedoukian, María José Sánchez-Soler, Oana Caluseriu, Katheryn Grand, Allison Tam, Alicia R.P. Aycinena, Letizia Camerota, Yiran Guo, Patrick Sleiman, Bert Callewaert, Candy Kumps, Annelies DheedeneMichael Buckley, Edwin P. Kirk, Anne Turner, Benjamin Kamien, Chirag Patel, Meredith Wilson, Tony Roscioli, John Christodoulou, Timothy C. Cox, Elaine H. Zackai, Francesco Brancati, Hakon Hakonarson, Elizabeth J. Bhoj

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1061-1076
Number of pages16
JournalHuman Genetics
Issue number7
Publication statusAccepted/In press - 2021

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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