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The Recurrent E-Cadherin (CDH1) Mutation c.760G>A Causes Orofacial Clefts but Does Not Predispose to Hereditary
Lea Gossner1, Dietmar Rieder2, Thomas Müller1
1Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Genes
|November 27, 2024
Summary
The recurrent CDH1 c.760G>A mutation strongly predisposes individuals to orofacial clefts (CL/P), particularly males. This specific mutation does not appear to increase the risk for hereditary diffuse gastric cancer (HDGC).
Area of Science:
- Genetics and Genomics
- Developmental Biology
- Medical Genetics
Background:
- Orofacial clefts (CL/P) are rarely caused by single gene mutations.
- Pathogenic CDH1 germline variants have been linked to non-syndromic CL/P and blepharocheilodontic syndrome.
- CDH1 encodes E-cadherin; numerous pathogenic variants are associated with hereditary diffuse gastric cancer (HDGC).
Purpose of the Study:
- To classify the phenotype associated with the CDH1 c.760G>A (p.Asp254Asn) mutation.
- To investigate the genotype-phenotype correlation of CDH1 variants in CL/P families.
Main Methods:
- Exome and Sanger sequencing were employed in a family with CL/P.
- A comprehensive review of pathogenic CDH1 variants was conducted using ClinVar, PubMed, and MEDLINE databases.
- Segregation analysis of the CDH1 c.760G>A variant within the affected family.
Main Results:
- The CDH1 c.760G>A variant was identified and segregated with bilateral CL/P in a family.
- This recurrent variant was previously reported in 21 individuals across six families, predominantly affecting males (16/16 males vs. 5/11 females).
- No gastrointestinal tumors were reported in heterozygous individuals, suggesting no increased risk for HDGC.
Conclusions:
- The CDH1 c.760G>A mutation confers a high risk for CL/P, with a significant male predominance.
- Evidence suggests this specific variant does not increase the risk for hereditary diffuse gastric cancer (HDGC).
- Distinguishing craniofacial phenotypes from cancer risks in CDH1 mutation carriers is crucial for precision medicine and genetic counseling.
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