Submission Details

The CDH3 gene was first reported in relation to autosomal recessive congenital hypotrichosis with juvenile macular dystrophy (HJMD) in 2001 (Sprecher et al., PMID: 11544476). Subsequently, it was reported in relation to autosomal recessive ectodermal dysplasia, ectrodactyly, and macular dystrophy (EEM) in 2005 (Kjaer et al., PMID: 15805154). Both HJMD and EEM are rare, and their common features are sparse hair and macular dystrophy of the retina. Only EEM syndrome shows the additional hand/foot malformation. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism AND inheritance pattern. The phenotypic variability of EEM may include JHMD and mild hand/foot malformation is a relative common finding in the general population. Therefore, HJMD (OMIM #601553) and EEM (OMIM #225280) have been lumped into one disease entity represented by EEM. Eight variants (missense, nonsense, frameshift, canonical splicing) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be LOF. This gene-disease association is also supported by expression studies showing P-cadherin encoded by CDH3 in hair follicle placode, pigmented epithelium of the retina, and apical ectodermal ridge in the limb bud (Shimomura et al., PMID: 18199584). In summary, CDH3 is definitively associated with autosomal recessive ectodermal dysplasia, ectrodactyly, and macular dystrophy (EEM). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.