CDH2 – Agenesis of Corpus Callosum, Cardiac, Ocular, and Genital Syndrome

Agenesis of Corpus Callosum, Cardiac, Ocular, and Genital Syndrome (ACOGS) is a multisystem disorder characterized by global developmental delay, corpus callosum agenesis or hypoplasia, craniofacial dysmorphism, ocular anomalies, cardiac defects, and genital malformations. CDH2 encodes the cell-adhesion protein N-cadherin, essential for neural development, cardiac morphogenesis, and urogenital tract formation. Germline variants in CDH2 have been causally linked to ACOGS through de novo heterozygous loss-of-function and missense mutations that disrupt intercellular adhesion.

To date, nine unrelated individuals harboring de novo CDH2 variants were reported in 2019, comprising seven missense and two frameshift alleles clustered in extracellular cadherin domains 4 and 5, and an additional case with a novel nonsense variant in 2022, totaling ten probands (PMID:31585109 and PMID:35708058). Variant spectrum includes c.1839C>G (p.Cys613Trp) among missense substitutions and frameshift alleles predicted to truncate the cytoplasmic tail. All variants arose de novo, supporting an autosomal dominant inheritance mode without evidence of transmitted segregation.

Functional studies demonstrate that missense and frameshift variants in CDH2 impair calcium-dependent cell aggregation in vitro, revealing a loss of N-cadherin adhesive function consistent with disruption of homophilic interactions (PMID:31585109). These defects correlate with impaired neuronal migration and axon pathfinding in model systems, recapitulating the corpus callosum anomalies and neurodevelopmental delay seen in patients.

No reports have contradicted the pathogenicity of CDH2 variants in ACOGS. Experimental concordance across cell-based adhesion assays and clinical clustering of alleles in critical EC domains reinforce the gene-disease link. The lack of familial segregation is offset by strong de novo evidence and consistent phenotypes in unrelated cases.

Integrating genetic and functional data, CDH2 has a strong ClinGen gene-disease association with ACOGS, supported by ten de novo cases and concordant mechanistic assays. The autosomal dominant mode of inheritance, variant clustering, and in vitro impairment of adhesion provide compelling evidence for pathogenicity.

Key Take-home: Heterozygous de novo CDH2 variants causing loss of N-cadherin adhesion lead to a distinctive multisystem syndrome—ACOGS—with clear diagnostic and mechanistic implications for genetic testing and counseling.

References

• American Journal of Human Genetics • 2019 • De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects. PMID:31585109
• American Journal of Medical Genetics Part A • 2022 • A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report. PMID:35708058

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