The characteristics of Waardenburg syndrome (WS) as a scarce heritable disorder are sensorineural hearing loss and deficits of pigmentation in the skin, hair, and eye. Here, clinical features and detection of the mutation in the MITF gene of WS2 patients are reported in a sizable Iranian family. A man aged 28-years represented with symptoms of mild unilateral hearing loss (right ear), complete heterochromia iridis, premature graying prior to 30 years of age, and synophrys. In this research, there was a sizable family in Iran comprising three generations with seven WS patients and two healthy members. Whole exome sequencing was applied for proband for the identification of the candidate genetic mutations associated with the disease. The detected mutation in proband and investigated family members was validated by PCR-Sanger sequencing. A novel heterozygous mutation, NM_198159.3:c.1026dup p.(Asn343Glufs*27), in exon 9 of the MITF gene co-segregated with WS2 in the affected family members. The variant was forecasted as a disease-causing variant by the Mutation Taster. According to the UniProt database, this variant has been located in basic helix-loop-helix (bHLH) domain of the protein with critical role in DNA binding. A frameshift was caused by a nucleotide insertion, c.1026dup, in exon 9 of the MITF gene. This mutation is able to induce an early termination, resulting in forming a truncated protein capable of affecting the normal function of the MITF protein. Helpful information is provided through an exactly described mutations involved in WS to clarify the molecular cause of clinical characteristics of WS and have a contribution to better genetic counseling of WS patients.

中文翻译：

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伊朗大家庭中的 2A 型瓦登堡综合征，具有新的 MITF 基因突变


瓦登堡综合征 (WS) 作为一种稀有遗传性疾病，其特征是感音神经性听力损失以及皮肤、头发和眼睛色素沉着缺陷。在此，报告了一个相当大的伊朗家庭中 WS2 患者的临床特征和 MITF 基因突变的检测。一名 28 岁男性，出现轻度单侧听力损失（右耳）、完全虹膜异色、 30 岁之前头发花白和一字性症状。在这项研究中，伊朗有一个相当大的家庭，由三代人组成，有七名 WS 患者和两名健康成员。对先证者进行全外显子组测序，以鉴定与疾病相关的候选基因突变。先证者和调查的家庭成员中检测到的突变通过 PCR-Sanger 测序进行了验证。受影响家族成员中与 WS2 共分离的 MITF 基因外显子 9 中存在新的杂合突变 NM_198159.3:c.1026dup p.(Asn343Glufs*27)。突变品尝者预测该变异为致病变异。根据 UniProt 数据库，该变体位于该蛋白的基本螺旋-环-螺旋 (bHLH) 结构域中，在 DNA 结合中发挥关键作用。移码是由 MITF 基因外显子 9 中的核苷酸插入 c.1026dup 引起的。这种突变能够诱导提前终止，从而形成能够影响 MITF 蛋白正常功能的截短蛋白。通过准确描述 WS 涉及的突变提供有用的信息，以阐明 WS 临床特征的分子原因，并有助于更好地对 WS 患者进行遗传咨询。