Division of Genetics, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
Am J Med Genet A. 2021 Jul;185(7):2056-2064. doi: 10.1002/ajmg.a.62217. Epub 2021 Apr 21.
Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder characterized by anomalies mainly involving the structures derived from the first and second pharyngeal arches. The spectrum presents with heterogeneous clinical features and complex etiology with genetic factors not yet completely understood. To date, MYT1 is the most important gene unambiguously associated with the spectrum and with functional data confirmation. In this work, we aimed to identify new single nucleotide variants (SNVs) affecting MYT1 in a cohort of 73 Brazilian patients diagnosed with OAVS. In addition, we investigated copy number variations (CNVs) encompassing this gene or its cis-regulatory elements and compared the frequency of these events in patients versus a cohort of 455 Brazilian control individuals. A new SNV, predicted as likely deleterious, was identified in five unrelated patients with OAVS. All five patients presented hearing impairment and orbital asymmetry suggesting an association with the variant. CNVs near MYT1, located in its neighboring topologically associating domain (TAD), were found to be enriched in patients when compared to controls, indicating a possible involvement of this region with OAVS pathogenicity. Our findings highlight the genetic complexity of the spectrum that seems to involve more than one variant type and inheritance patterns.
眼-耳-脊椎发育不良谱（OAVS）是一种发育障碍，其特征为主要涉及第一和第二咽弓衍生结构的异常。该谱表现出异质的临床特征和复杂的病因，遗传因素尚未完全了解。迄今为止，MYT1 是与该谱最明确相关的最重要基因，并具有功能数据的确认。在这项工作中，我们旨在鉴定新的单核苷酸变异（SNVs）影响 MYT1 在 73 例巴西患者的队列中诊断为 OAVS。此外，我们研究了包含该基因或其顺式调控元件的拷贝数变异（CNVs），并比较了这些事件在患者与 455 名巴西对照个体中的频率。在五个不相关的 OAVS 患者中发现了一个新的 SNV，预测为可能有害。所有五个患者均表现出听力障碍和眶不对称，提示与该变异有关。与对照相比，位于 MYT1 附近的 CNVs （位于其邻近的拓扑关联域（TAD）中）在患者中富集，表明该区域可能与 OAVS 的发病机制有关。我们的研究结果强调了该谱的遗传复杂性，似乎涉及多种变异类型和遗传模式。
