Novel PAX3 splice-site variant in a woman with Waardenburg syndrome

Reiner, O. (2025). Novel PAX3 splice-site variant in a woman with Waardenburg syndrome (Version 1) [DataSet]. GestaltMatcher Database.

We report a case 36-year-women who presented with unilateral congenital sensorineural hearing loss, dystopia canthorum (W index of 2,11), complete hair hypopigmentation which started as a white forelock during puberty, complete heterochromia iridium and patchy Skin hypopigmentation on her abdomen and right forearm. No skeletal malformations of the limbs were present. Together, the symptoms allowed establishing the clinical diagnosis of Waardenburg syndrome type 1 according to the Waardenburg Consortium criteria. Gene panel sequencing revealed a novel heterozygous splice-site variant (NM181458.4:c.85+1G>T) in PAX3 predicted to affect the PAI subdomain, which we consequently classified as likely pathogenic (ACMG criteria PVS1S, PP4), confirming the clinical diagnosis. The Patient reported premature gray hair without additional symptoms in both her mother and maternal grandmother, raising a possibility of an inherited variant with variable expressivity and a significantly milder phenotype without dystopia canthorum in the family. Testing of further family members was pending at time of reporting.