Genetic and functional analysis of CDH2 reveals new insights into CDH2-related disorders

Pathogenic variants in CDH2 cause agenesis of the corpus callosum, cardiac, ocular, and genital syndrome (ACOGS). We aimed to define the clinical and molecular landscape of CDH2-related developmental disorders.

Newly identified and previously reported families were analyzed for genotype-phenotype correlations; variants were assessed using protein modeling and splicing assays.

Screening identified 20 new families carrying (likely) pathogenic ((L)P) alleles (n=16) or high-priority variants of uncertain significance (VUS) (n=4), including 12 novel CDH2 alleles. The combined (L)P cohort (37 individuals) showed variable ACOGS core features (mean 3; range 1-5), along with abdominal wall and/or diaphragmatic hernias and nipple, spine or gastrointestinal anomalies, each seen in ∼20% of individuals. Novel ACOGS findings included ambiguous genitalia, female genital malformations and dilated cardiomyopathy. Missense variants, principally within extracellular cadherin domains, accounted for 86% of unique (L)P alleles with clusters in EC1 and EC4-EC5; the remainder produce late protein truncations or in-frame deletions. Disruption of calcium binding was predicted by modeling. Conversely, VUS were primarily nonsense-mediated decay-sensitive or deletions (71%), linked to neurodevelopmental, kidney or other anomalies.

We expand the ACOGS spectrum and highlight its striking clinical variability. Additionally, we identify a possible milder phenotype associated with CDH2 haploinsufficiency.