CDH11

Inheritance Pattern: AR

Disease ID:MONDO:0008885

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0030674

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0008885

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030674

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030674

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0008885

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0008885

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0030674

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0008885

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0008885

Submitter: Ambry Genetics