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

CDH2

Missense variants in the extracellular cadherin domains of CDH2 (clusters in EC1 and EC4-EC5), predicted to disrupt calcium binding; haploinsufficiency possibly linked to a milder phenotype

This study combines 20 new families with previously published ones to define the clinical and molecular spectrum of CDH2-related disorders, which cause ACOGS (agenesis of the corpus callosum, cardiac, ocular and genital syndrome). Screening identified 16 pathogenic or likely pathogenic alleles and 4 high-priority variants of uncertain significance, including 12 novel alleles. In the combined cohort of 37 individuals with a pathogenic or likely pathogenic variant, the number of core features ranged from 1 to 5 (mean 3), and abdominal wall or diaphragmatic hernias and nipple, spine or gastrointestinal anomalies were each seen in about 20%; ambiguous genitalia, female genital malformations and dilated cardiomyopathy are newly reported. Missense variants, clustered in the extracellular cadherin domains, accounted for 86% of unique pathogenic alleles, whereas variants of uncertain significance were mostly NMD-sensitive variants or deletions (71%), linked to neurodevelopmental, kidney or other anomalies.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Useful delineation work: ACOGS is driven mainly by missense variants in the extracellular cadherin domains, predicted to disrupt calcium binding, rather than by loss of function. The consequence for exome or genome interpretation: an NMD-sensitive truncating CDH2 variant should not be attributed to ACOGS by default, and the milder phenotype suggested for haploinsufficiency remains to be confirmed. Functional evidence is limited to protein modelling and splicing assays.

Analysis by Dr Thibaut Benquey