Genetic and functional analysis of CDH2 reveals new insights into CDH2-related disorders.
Abstract
Purpose
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.
Methods
Newly identified and previously reported families were analyzed for genotype-phenotype correlations; variants were assessed using protein modeling and splicing assays.
Results
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.
Conclusion
We expand the ACOGS spectrum and highlight its striking clinical variability. Additionally, we identify a possible milder phenotype associated with CDH2 haploinsufficiency.