Waardenburg Syndrome: The Contribution of Next-Generation Sequencing to the Identification of Novel Causative Variants

IF 2.1 Q1 AUDIOLOGY & SPEECH-LANGUAGE PATHOLOGY

Audiology Research Pub Date : 2023-12-21 DOI:10.3390/audiolres14010002

William Bertani-Torres, Karina Lezirovitz, Danillo Alencar-Coutinho, Eliete Pardono, S. S. da Costa, Larissa do Nascimento Antunes, Judite de Oliveira, Paulo Alberto Otto, V. Pingault, R. Mingroni-Netto

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Abstract

Waardenburg syndrome (WS) is characterized by hearing loss and pigmentary abnormalities of the eyes, hair, and skin. The condition is genetically heterogeneous, and is classified into four clinical types differentiated by the presence of dystopia canthorum in type 1 and its absence in type 2. Additionally, limb musculoskeletal abnormalities and Hirschsprung disease differentiate types 3 and 4, respectively. Genes PAX3, MITF, SOX10, KITLG, EDNRB, and EDN3 are already known to be associated with WS. In WS, a certain degree of molecularly undetected patients remains, especially in type 2. This study aims to pinpoint causative variants using different NGS approaches in a cohort of 26 Brazilian probands with possible/probable diagnosis of WS1 (8) or WS2 (18). DNA from the patients was first analyzed by exome sequencing. Seven of these families were submitted to trio analysis. For inconclusive cases, we applied a targeted NGS panel targeting WS/neurocristopathies genes. Causative variants were detected in 20 of the 26 probands analyzed, these being five in PAX3, eight in MITF, two in SOX10, four in EDNRB, and one in ACTG1 (type 2 Baraitser-Winter syndrome, BWS2). In conclusion, in our cohort of patients, the detection rate of the causative variant was 77%, confirming the superior detection power of NGS in genetically heterogeneous diseases.

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瓦登堡综合征：下一代测序对鉴定新型致病变异的贡献

瓦登堡综合征（WS）的特征是听力损失以及眼睛、头发和皮肤的色素异常。这种疾病在遗传上具有异质性，临床上可分为四种类型，1 型患者有耳聋，2 型患者没有耳聋。此外，肢体肌肉骨骼异常和赫氏病也可分别区分为 3 型和 4 型。已知 PAX3、MITF、SOX10、KITLG、EDNRB 和 EDN3 基因与 WS 有关。在 WS 中，仍存在一定程度的分子检测不到的患者，尤其是 2 型患者。本研究旨在使用不同的 NGS 方法，在可能/疑似诊断为 WS1（8 例）或 WS2（18 例）的 26 例巴西疑似患者中找出致病变体。首先对患者的 DNA 进行外显子组测序分析。其中有 7 个家庭接受了三组分析。对于未确诊的病例，我们采用了针对 WS/神经顽疾基因的靶向 NGS 小组。在所分析的 26 个病例中，有 20 个检测到了致病变异，其中 PAX3 变异 5 个，MITF 变异 8 个，SOX10 变异 2 个，EDNRB 变异 4 个，ACTG1 变异 1 个（2 型巴雷泽-温特综合征，BWS2）。总之，在我们的患者队列中，致病变异的检出率为 77%，证实了 NGS 在遗传异质性疾病中的卓越检测能力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Audiology Research AUDIOLOGY & SPEECH-LANGUAGE PATHOLOGY-

CiteScore

2.30

自引率

23.50%

发文量

审稿时长

11 weeks

期刊介绍： The mission of Audiology Research is to publish contemporary, ethical, clinically relevant scientific researches related to the basic science and clinical aspects of the auditory and vestibular system and diseases of the ear that can be used by clinicians, scientists and specialists to improve understanding and treatment of patients with audiological and neurotological disorders.