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

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 Ca 2+ 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 CDH11related THS.

A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature

“…The phenotypes of individuals with AMOTL1 variants affecting amino acids 157 and neighboring residues overlap with other well‐known syndromes such as Hardikar syndrome [MIM #301068] caused by pathogenic nonsense and frameshift variants in MED12 (Li et al, 2021a, 2021b), Opitz GBBB syndrome [MIM #300000] caused by loss of function variants in MID1 (Cox et al, 2000), Teebi hypertelorism syndrome [MIM #145420] caused by pathogenic variants in SPECC1L and CDH11 (Bhoj et al, 2015; Li et al, 2021a, 2021b), and Simpson‐Golabi Behmel syndrome [MIM #312870] caused by pathogenic variants in GPC3 (Pilia et al, 1996). Of note, many of these genes are similarly implicated in YAP signaling, β‐catenin signaling, adherens junctions, cytoskeletal organization, and cell migration, consistent with a shared mechanism of disrupted cell signaling and migration at the heart of clefting syndromes (Bhoj et al, 2019; Galli et al, 2015; Kolluri & Ho, 2019; Saadi et al, 2011; Wilson et al, 2016).…”

“…The phenotypes of individuals with AMOTL1 variants affecting amino acids 157 and neighboring residues overlap with other wellknown syndromes such as Hardikar syndrome [MIM #301068] caused by pathogenic nonsense and frameshift variants in MED12 (Li et al, 2021a(Li et al, , 2021b, Opitz GBBB syndrome [MIM #300000] caused by loss of function variants in MID1 (Cox et al, 2000), Teebi hypertelorism syndrome [MIM #145420] caused by pathogenic variants in SPECC1L and CDH11 (Bhoj et al, 2015;Li et al, 2021aLi et al, , 2021b, and…”

Hereditary dentin defects with systemic diseases

“…Calcium‐dependent cell adhesion protein Cadherin‐11 (CDH11) is encoded by CDH11 and preferentially interacts with itself in a homophilic manner in connective cells. Therefore, cadherins contribute to the sorting of heterogeneous cell types and are involved in the regulation of cell migration (Li et al, 2021).…”

A Japanese patient with Teebi hypertelorism syndrome and a novel CDH11 EC1 domain variant

“…The data are not publicly available due to privacy or ethical restrictions. a Li et al, 2021. b Castori et al, 2018Harms et al, 2018;Minatogawa et al, 2021;Taskiran et al, 2017.…”

“…Furthermore, heterozygous CDH11 ‐dominant negative variants have been associated with Teebi hypertelorism syndrome (THS; OMIM#619736). Nine THS families have been reported with widely spaced eyes and hypospadias (Li et al, 2021). In this study, we present a THS patient with a novel heterozygous CDH11 variant.…”