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

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 (NM_181458.4:c.85+1G>T) in PAX3 predicted to affect the PAI subdomain, which we consequently classified as likely pathogenic (ACMG criteria PVS1_S, 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.

本研究报道1例36岁女性患者，其临床表现为单侧先天性感音神经性听力损失（unilateral congenital sensorineural hearing loss）、内眦距过宽（dystopia canthorum，W指数为2.11）、青春期始发的全身性毛发色素减退（初始表现为前额白发）、完全性虹膜异色症（complete heterochromia iridium），且腹部与右前臂存在片状皮肤色素减退。患者未出现肢体骨骼畸形。结合上述症状，依据瓦登伯革联盟诊断标准，可确诊为瓦登伯革综合征1型（Waardenburg syndrome type 1）。基因panel测序（gene panel sequencing）检测发现PAX3基因中存在1个新发杂合剪接位点变异（NM_181458.4:c.85+1G>T），经预测该变异可影响PAI亚结构域，依据美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics, ACMG）标准PVS1_S、PP4，将其归类为疑似致病性变异，进一步验证了临床诊断。该患者自述其母亲及外祖母均存在早发性白发，无其他相关症状，提示该家系中可能携带具有可变外显率的遗传性变异，且该变异对应的表型更为轻微，无内眦距过宽症状。本报道撰写时，更多家族成员的基因检测工作尚未完成。