A homozygous variant in the GJB2 gene as a potential phenocopy of Waardenburg syndrome: case report

Waardenburg syndrome (WS) is a neurocristopathy primarily characterized by congenital hearing loss and multisystem pigmentary abnormalities. We report a 12-year-old Han Chinese girl who presented with moderate-to-severe sensorineural hearing loss, a wide nasal root, diffuse hypopigmentation of the hair, and facial freckles—features partially similar to the WS phenotype. However, her calculated W-index was 1.87, below the diagnostic threshold for dystopia canthorum (>1.95), and her overall clinical presentation did not meet the diagnostic criteria for any WS subtype. Whole-exome sequencing (WES) and subsequent familial Sanger sequencing identified a homozygous GJB2 variant, c.109G > A (p.Val37Ile), in the proband, with both parents confirmed as heterozygous carriers. Based on the integrated clinical and genetic evidence, the patient was diagnosed with GJB2 -related autosomal recessive nonsyndromic hearing loss (DFNB1A). Her WS-like features were interpreted as a possible phenocopy. This case highlights that in patients with hearing loss exhibiting incomplete or atypical WS features, comprehensive genetic testing—including analysis of GJB2 —is crucial to differentiate phenocopies, establish an accurate etiology, and provide a basis for precise diagnosis and genetic counseling.