Submission Details

The CDH11 gene located on chromsome 16 at 16q21 encodes a type II classical cadherin from the cadherin superfamily, integral membrane proteins that mediate calcium-dependent cell-cell adhesion. The protein is composed of 5 extracellular cadherin domains, one transmembrane domain, and one intracellular domain (Harms 2018). CDH11 was first reported in relation to Teebi hypertelorism syndrome 2 (TBHS2), also known as brachycephalofrontonasal dysplasia, in 2021 (Li et al., 2021 PMID: 33811546). TBHS2 is characterized by hypertelorism, cardiac and genitourinary defects. Intellectual disability and other craniofacial dysmorphism tends to be rarer and milder than the autosomal recessive condition also caused by variants in CDH11, Elsahy-Waters syndrome (ESWS; OMIM:211380). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms, inheritance patterns, and phenotypic variability among individuals with biallelic versus monoallelic CDH11 variants. Therefore, the following disease entities have been split into multiple disease entities, AR Elsahy-Waters syndrome (ESWS) (OMIM:211380), and AD Teebi hypertelorism syndrome 2 (OMIM:619736). The split curation for AR Elsahy-Waters syndrome (ESWS) (OMIM:211380) has been curated separately. Other presenting features of TBHS2 include broad or short phalanx, large anterior fontanelle, and umbilical defects. All variants reported to date are missense variants impacting the extracellular domains. Ten probands (6 de novo, 4 consistent with AD inheritance) from two publications are included in this curation (Li 2021, PMID: 33811546; Kuroda 2024, PMID: 37646430). The mechanism of pathogenicity is unclear. This gene-disease relationship is also supported by experimental evidence including mouse models which partially recapitulate the TBHS2 phenotype, particularly with respect to cranial dysmorphology and cardiac defects (Alimperti et al., 2014 PMID: 24741067; Bowen et al., 2015 PMID: 26188246), but these present an inheritance mismatch and likely a molecular mechanism mismatch between homozygous null mice and heterozygous missense human patients. Missense functional alterations in patient fibroblasts show higher CDH11 expression than wild type controls , and transfected L cells with missense changes found in patients display adhesion and migration defects, suggesting a possible gain of function or dominant negative molecular mechanism of pathogenicity ( PMID: 33811546). In summary, there is moderate evidence supporting the relationship between CDH11 and AD TBHS2. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date May 17th, 2024 (SOP Version 10).