Submission Details

The CDH11 gene located on chromosome 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. CDH11 was first reported in relation to Elsahy-Waters syndrome (ESWS), also known as branchioskeletogenital syndrome, in 2016 (Anazi et al., 2016 PMID: 27431290). ESWS is characterized by significant craniofacial dysmorphism (including hypertelorism, broad forehead, thick eyebrows with synophrys, flat malar regions, broad/ bulbous noses, mild prognathism), multiple congenital ocular, dental, digital, genital and vertebral anomalies, moderate intellectual disability and/or moderate hearing loss. 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 (TBHS2) (OMIM:619736). The split curation for AD TBHS2 has been curated separately. All variants reported to date in the recessive condition are putative loss of function variants, including nonsense, frameshifts, essential splice donor and/or acceptor variants impacting the extracellular domains. Five homozygous probands from consanguineous families in five publications have been included in this curation (PMID:27431290; Taskiran et al., 2017 PMID: 28988429; Harms et al., 2018 PMID: 29271567; Castori et al., 2018 PMID: 30194892; Minatogawa et al., 2021 PMID: 34278706). The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by functional alteration of patient cells (PMID: 28988429) and several homozygous null animal models recapitulating cranial, femoral, and snout dysmorphology (Kawaguchi et al., 2001 PMID: 11450702), hearing loss (Kiyama et al., 2018 PMID: 29967341), and genitourinary malformations (IMPC database, Dickinson et al., 2016 PMID: 27626380). In summary, there is definitive evidence supporting the relationship between CDH11 and AR ESWS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date May 17th, 2024 (SOP Version 10).