The aim of the CDH1-associated Blepharocheilodontic Syndrome (BCDS) registry is to better characterize the clinical features of this condition and exploring whether CDH1 variants linked to BCDS may also increase cancer risk.

Blepharocheilodontic Syndrome (BCDS) is a rare genetic disorder characterized by cleft lip and/or palate (CL/P), eyelid malformations, and features suggestive of ectodermal dysplasia. Variants in the CDH1 gene, which encodes the cell adhesion protein E-cadherin, have been implicated in BCDS. Functional studies have demonstrated that CDH1 plays a critical role in lip and palate development during embryogenesis (Ghoumid 2017; Figueiredo 2019).

In the hereditary cancer genetics community, CDH1 is more commonly associated with hereditary diffuse gastric and lobular breast cancer syndrome (DGLBC). CDH1 variants linked to DGLBC are typically truncating mutations, resulting in a null allele. In contrast, CDH1 variants observed in individuals with BCDS are often missense mutations located in the EC1-EC2 linker region (amino acids 254-257) or exon 9 donor splice site variants (e.g., c.1320G>T, c.1320+1G>A, c.1320+1G>T, c.1320+1G>C, c.1320+5G>A) (Ghoumid 2017; Kievit 2018).

Historically, it was believed that individuals with BCDS-associated CDH1 missense variants were not at increased risk for DGLBC-associated cancers. This assumption was based on the absence of reported cancer cases in published BCDS families and epidemiological data from the CDH1 ClinGen Variant Curation Expert Panel (VCEP), which suggested that missense variants may not confer elevated cancer risk (Ghoumid 2017; Kievit 2018; Lee 2018).

However, a 2020 case report by LeBlanc et al. described a family with a known BCDS-associated CDH1 missense variant (c.768T>A, p.N256K), in which a 37-year-old male developed diffuse gastric cancer. This report raised concerns about potential cancer risks in individuals with BCDS-associated CDH1 variants and prompted questions regarding the need for endoscopic screening and other surveillance measures.

Currently, data regarding cancer risk in individuals with CDH1 variants and the BCDS phenotype are limited. The condition is rare, and affected individuals are often identified through exome sequencing due to multiple congenital anomalies. The interpretation of familial cancer risk is further complicated by a high rate of de novo mutations and limited family history.

To address these gaps, this registry aims to establish a centralized, international cohort of individuals with CDH1-associated BCDS. The goal is to better characterize the genotype-phenotype correlations, define the clinical spectrum, and assess the potential cancer risks associated with these variants.

Inclusion Criteria:

• A documented pathogenic, likely pathogenic or a variant of uncertain significance in the CDH1 gene
• Clinical features that are diagnostic for, or suggestive of, BCDS (cleft lip and/or palate, eyelid anomalies, dental abnormalities, webbed toes, imperforate anus, etc)

Exclusion Criteria:

• Non-English-speaking individuals

Study participation is not limited by location. There are two ways eligible patients can be referred:

• Provider referral: The registry can be discussed with the potential study participant, and if they're interested, verbal permission can be obtained for our study team to reach out. With their consent, the study participant's name and preferred contact information can be sent to bcdsregistry@osumc.edu.
• Self-referral: Potential study participants can express interest in study participation by visiting the registry website (https://redcap.link/BCDSregistry).

Individual participant data will not be broadly shared. However, external requests for data access may be considered for use in downstream research protocols. All such requests must include an IRB-approved protocol and a formal application for data use. The BCDS Registry Advisory Board, comprising the Principal Investigator and at least one co-investigator, will review applications based on scientific merit and relevance, with input from a statistician as needed.

For approved requests, data will be shared via a secure "data push," typically involving export from REDCap to a coded-limited file format. The individual responsible for data transfer will be certified as an honest broker under the OSUWMC Honest Broker Protocol. All studies using registry data will be conducted under separate IRB oversight.

Beginning after study accrual has reached 20 with no end date

All research studies, whether internal or external to The Ohio State University, using data from the CDH1-associated BCDS Registry must be conducted under separate IRB approvals. Interested collaborators should email bcdsregistry@osumc.edu to request an Application for Use of Data. The application must include documentation of an IRB-approved protocol describing the proposed use of the data.