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

Abstract

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.