TY - JOUR
T1 - Pathogenic variants in CDH11 impair cell adhesion and cause Teebi hypertelorism syndrome
AU - Li, Dong
AU - March, Michael E.
AU - Fortugno, Paola
AU - Cox, Liza L.
AU - Matsuoka, Leticia S.
AU - Monetta, Rosanna
AU - Seiler, Christoph
AU - Pyle, Louise C.
AU - Bedoukian, Emma C.
AU - Sánchez-Soler, María José
AU - Caluseriu, Oana
AU - Grand, Katheryn
AU - Tam, Allison
AU - Aycinena, Alicia R.P.
AU - Camerota, Letizia
AU - Guo, Yiran
AU - Sleiman, Patrick
AU - Callewaert, Bert
AU - Kumps, Candy
AU - Dheedene, Annelies
AU - Buckley, Michael
AU - Kirk, Edwin P.
AU - Turner, Anne
AU - Kamien, Benjamin
AU - Patel, Chirag
AU - Wilson, Meredith
AU - Roscioli, Tony
AU - Christodoulou, John
AU - Cox, Timothy C.
AU - Zackai, Elaine H.
AU - Brancati, Francesco
AU - Hakonarson, Hakon
AU - Bhoj, Elizabeth J.
N1 - Funding Information:
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.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85103626195&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103626195&partnerID=8YFLogxK
U2 - 10.1007/s00439-021-02274-3
DO - 10.1007/s00439-021-02274-3
M3 - Article
AN - SCOPUS:85103626195
VL - 140
SP - 1061
EP - 1076
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 7
ER -