CTNND1 – Blepharocheilodontic Syndrome

Blepharocheilodontic syndrome is an autosomal dominant disorder characterized by eyelid malformations, orofacial clefts and ectodermal dysplasia. Heterozygous truncating variants in CTNND1 have been identified in 19 unrelated probands, including six de novo events, across at least nine families, with no variants observed in healthy parents (PMID:28301459; PMID:32196547; PMID:37274823). Segregation analysis in familial cases confirms co-segregation with disease.

Genetic evidence supports a haploinsufficiency mechanism: 15 distinct truncating or frameshift alleles cluster throughout the coding region and are absent from large population cohorts. A recurrent variant c.1093C>T (p.Gln365Ter) was observed in multiple families, demonstrating independent occurrence and pathogenicity (PMID:28301459).

Functional studies demonstrate that conditional knockout of Ctnnd1 in mouse and Xenopus induces craniofacial, eyelid and tooth anomalies mirroring the human phenotype, and that loss of p120-catenin disrupts the E-cadherin–p120ctn complex essential for epithelial integrity (PMID:28301459; PMID:29348693). Cellular assays confirm accelerated E-cadherin degradation and impaired cell–cell adhesion consistent with a loss-of-function mechanism.

No conflicting evidence has been reported that disputes CTNND1’s role in blepharocheilodontic syndrome. All documented pathogenic variants are truncating and segregate with disease in an autosomal dominant fashion.

In conclusion, CTNND1 meets criteria for a Strong clinical validity classification based on 19 probands, de novo occurrences, segregation data and concordant animal and cellular models. Identification of truncating CTNND1 variants is clinically actionable for diagnosis, genetic counseling and prenatal testing in families affected by blepharocheilodontic syndrome.

References

• Genetics in medicine • 2017 • Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1 PMID:28301459
• European journal of human genetics • 2018 • Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome PMID:29348693
• Human molecular genetics • 2020 • Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome PMID:32196547
• Frontiers in pediatrics • 2023 • Major fetal cardiac pathology associated with a novel CTNND1 mutation PMID:37274823

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