Revisiting the <scp>W</scp> ‐Index and Waardenburg Syndrome: A Retrospective Review of Waardenburg Syndrome Diagnoses at a Single Site Hearing Loss Clinic and the Sensitivity, Specificity, and Genotype–Phenotype Correlations of an Elevated <scp>W</sc

Waardenburg syndrome (WS) is a genetically heterogenous condition characterized by variable clinical features including congenital sensorineural hearing loss, pigmentation differences, dysmorphic features including dystopia canthorum, and other manifestations. Pathogenic variants in WS genes, including PAX3, MITF, SOX10, EDNRB, EDN3, and KITLG, account for approximately 3% of congenital hearing loss cases. The genetic heterogeneity, variable expressivity, and different subtypes of WS have made diagnosis challenging. Recent literature suggests that W-index measurements evaluating for dystopia canthorum may not accurately differentiate between WS Types 1 and 2. This retrospective chart review investigated genotype-phenotype correlations in patients with WS at the Children's Hospital of Philadelphia. This study included 56 patients with a clinical or genetic diagnosis of WS. In addition, data was collected from 1744 patients with hearing loss and W-index measurements. Phenotypic characteristics were recorded for all 56 patients and an additional 230 patients with an elevated W-index (> 1.95) lacking a diagnosis of WS to determine the predictiveness of the W-index for WS. This study updates genotype-phenotype correlations in WS, characterizes novel variants, investigates the utility and predictiveness of W-index values in children with hearing loss, and provides rationale for increasing the W-index cutoff for dystopia canthorum to reduce negative testing results.