First CDH3-related HJMD case in a black patient: novel variants and diagnostic odyssey

Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive disorder caused by pathogenic variants in the CDH3 gene. Most reported cases have occurred in Middle Eastern and Asian populations, and individuals of African ancestry remain markedly underrepresented in inherited retinal disease cohorts and genomic reference databases. Here, we report the first published case of suspected CDH3-related HJMD in a Black patient.

Clinical evaluation included visual acuity, fundus examination, and SD-OCT. Genome sequencing was performed with copy number variant analysis and in silico tools were used to predict pathogenicity. Maternal segregation analysis was also performed.

The patient presented in childhood with progressive central macular atrophy and longstanding scalp hypotrichosis, but early genetic testing suggested an alternative diagnosis. Subsequent whole-exome sequencing identified two heterozygous variants in CDH3: an unreported exon 2 deletion (chr16:68679423_68691379) predicted to cause loss of P-cadherin protein function and classified as likely pathogenic under ACMG criteria, and an extremely rare missense variant (c.1658T > A; p.(Ile553Asn)) classified as a variant of uncertain significance but predicted by in silico modeling to destabilize P-cadherin.

With the patient's characteristic syndromic presentation, these findings supported a clinical diagnosis of HJMD. This case underscores the importance of careful phenotyping and reevaluation with updated comprehensive genomic testing when initial results are nondiagnostic or inconsistent with presentation. Documenting rare CDH3 variants in an underrepresented population contributes to the expanding mutation spectrum of CDH3 and may improve future genotype-phenotype interpretation.