Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India.
Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Cochin, India.
Clin Genet. 2019 Mar;95(3):398-402. doi: 10.1111/cge.13468. Epub 2018 Nov 27.
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.
瓦登伯格综合征（WS）是一种神经嵴细胞迁移障碍，其特征为听觉和色素异常。我们通过靶向测序或全外显子组测序研究了 14 个家系（16 名受试者）。其中 13 个家系被临床诊断为 WS，1 个家系为孤立性非综合征性听力损失（NSHL）。在分别携带 PAX3、MITF 和 EDNRB 致病性变异的 WS1、WS2 和 WS4 家系中观察到了家族内表型变异性和非外显率。我们观察到一个无症状的两位受影响兄弟姐妹的父亲存在 PAX3 变异的性染色体嵌合体。这是首次在 WS2 患者中报告 MITF 中的双等位基因致病性变异，在 WS2 患者中也注意到 EDNRB 的双等位基因变异。孤立性 NSHL 患者携带 MITF 中的致病性变异。在临床上被诊断为 WS2 的患者中观察到 NSHL 和白化病的混合表型。在一个报告 GJB2 致病性变异的患者中观察到 WS1 的表型类似物，该基因已知可导致孤立性 NSHL。这些新的和罕见报道的观察结果说明了 WS 的等位基因和遗传异质性，并显示了 WS 的表型多样性。
