Locus and allelic heterogeneity and phenotypic variability in Waardenburg syndrome

Waardenburg syndrome (WS) is a disorder of neural crest cell migration characterized by auditory and pigmentary abnormalities. We investigated a cohort of 14 families (16 subjects) either by targeted sequencing or whole‐exome sequencing. Thirteen of these families were clinically diagnosed with WS and one family with isolated non‐syndromic hearing loss (NSHL). Intra‐familial phenotypic variability and non‐penetrance were observed in families diagnosed with WS1, WS2 and WS4 with pathogenic variants in PAX3 , MITF and EDNRB , respectively. We observed gonosomal mosaicism for a variant in PAX3 in an asymptomatic father of two affected siblings. For the first time, we report a biallelic pathogenic variant in MITF in a subject with WS2 and a biallelic variant in EDNRB was noted in a subject with WS2. An individual with isolated NSHL carried a pathogenic variant in MITF . Blended phenotype of NSHL and albinism was observed in a subject clinically diagnosed to have WS2. A phenocopy of WS1 was observed in a subject with a reported pathogenic variant in GJB2 , known to cause isolated NSHL. These novel and infrequently reported observations exemplify the allelic and genetic heterogeneity and show phenotypic diversity of WS.