Novel Compound Heterozygous Variants in CDH3 Cause Congenital Hypotrichosis with Juvenile Macular Dystrophy: A Case...

Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive disorder caused by biallelic CDH3 variants. We report a Chinese patient with HJMD carrying novel compound heterozygous CDH3 variants, providing functional validation and longitudinal imaging documentation of disease progression.

We present an 18-year-old male with painless bilateral vision loss over 8 years and sparse scalp hair noted since 5 years of age. Multimodal imaging documented a severe maculopathy that progressed from outer retinal tubulations (ORTs) to diffuse atrophy within 2 years, accompanied by choroidal thinning and reduced choriocapillaris perfusion. The patient also exhibited the characteristic hypotrichosis. Whole exome sequencing revealed novel compound heterozygous variants in CDH3, including an intronic splicing variant c.391-3C>G, and a missense variant c.1625A>G (p.Asn542Ser), suggesting a diagnosis of HJMD. The minigene splice assay provided evidence that c.391-3C>G leads to aberrant splicing with intron 4 retention and exon 5 skipping. Structural modeling suggested that p.Asn542Ser disrupts a key hydrogen bond in the fourth extracellular cadherin repeat domain, potentially destabilizing the extracellular structure of P-cadherin.

This case demonstrates that intronic CDH3 variants require functional validation for accurate diagnosis, and that ORTs in HJMD can progress rapidly to diffuse atrophy, highlighting a potential window for future interventions.