Table_1_Case Report: A Novel Gross Deletion in PAX3 (10.26 kb) Identified in a Chinese Family With Waardenburg Syndrome by Third-Generation Sequencing.DOCX

Waardenburg syndrome (WS) is a group of autosomal-dominant hereditary conditions with a global incidence of 1/42,000. WS can be categorized into at least four types: WS1–4, and these are characterized by heterochromia iridis, white forelock, prominent nasal root, dystopia canthorum, hypertrichosis of the medial part of the eyebrows, and deaf-mutism. WS3 is extremely rare, with a unique phenotype (upper limb abnormality). Heterozygous mutations of PAX3 are commonly associated with WS1, whereas partial or total deletions of PAX3 are often observed in WS3 cases. Deletions, together with insertions, translocations, inversions, mobile elements, tandem duplications, and complexes, constitute structural variants (SVs), which can be fully and accurately detected by third-generation sequencing (TGS), a new generation of high-throughput DNA sequencing technology. In this study, after failing to identify the causative gene by Sanger sequencing, SNP-array, and whole-exome sequencing (WES), we finally detected a heterozygous gross deletion of PAX3 (10.26kb, chr2: 223153899-223164405) in a WS family by TGS. Our description would enrich the genetic map of WS and help us to further understand this disease. Our findings also demonstrated the value of TGS in clinical genetics researches.

瓦尔德内尔综合征（Waardenburg syndrome，简称 WS）是一组常染色体显性遗传性疾病，全球发病率约为 1/42,000。该综合征可被划分为至少四种类型：WS1-4，其特征包括异色性虹膜、白发刘海、鼻根突出、眼角外翻、眉内侧多毛以及聋哑。其中 WS3 类型极为罕见，具有独特的表型（上肢畸形）。PAX3 基因的杂合突变通常与 WS1 相关，而 PAX3 的部分或完全缺失则在 WS3 患例中较为常见。缺失、插入、易位、倒位、移动元件、串联重复以及复合结构构成了结构变异（SVs），这些变异可通过第三代测序（TGS）这一新一代高通量DNA测序技术进行完全且精确的检测。在本研究中，我们经过桑格测序、SNP-array 和全外显子测序（WES）未能识别出致病基因后，最终通过 TGS 在一个 WS 家族中检测到 PAX3 基因的杂合大片段缺失（10.26kb，chr2: 223153899-223164405）。我们的描述将丰富 WS 的遗传图谱，并有助于我们进一步理解该疾病。我们的发现也证明了 TGS 在临床遗传学研究中的价值。