Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, 20054 Segrate, Italy.
Unità di Neuro-Oncologia Molecolare, Fondazione IRCCS, Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
Int J Mol Sci. 2022 Sep 2;23(17):10017. doi: 10.3390/ijms231710017.
Neurofibromatosis type 2 is an autosomal dominant tumor-prone disorder mainly caused by point mutations or intragenic deletions. Few individuals with a complex phenotype and 22q12 microdeletions have been described. The 22q12 microdeletions' pathogenic effects at the genetic and epigenetic levels are currently unknown. We here report on 22q12 microdeletions' characterization in three NF2 patients with different phenotype complexities. A possible effect of the position was investigated by in silico analysis of 22q12 topologically associated domains (TADs) and regulatory elements, and by expression analysis of 12 genes flanking patients' deletions. A 147 Kb microdeletion was identified in the patient with the mildest phenotype, while two large deletions of 561 Kb and 1.8 Mb were found in the other two patients, showing a more severe symptomatology. The last two patients displayed intellectual disability, possibly related to gene deletion. The microdeletions change from one to five TADs, and the 22q12 chromatin regulatory landscape, according to the altered expression levels of four deletion-flanking genes, including , are likely associated with an early ischemic event occurring in the patient with the largest deletion. Our results suggest that the identification of the deletion extent can provide prognostic markers, predictive of NF2 phenotypes, and potential therapeutic targets, thus overall improving patient management.
神经纤维瘤病 2 型是一种常染色体显性遗传的肿瘤易感性疾病，主要由点突变或基因内缺失引起。已经描述了少数具有复杂表型和 22q12 微缺失的个体。22q12 微缺失在遗传和表观遗传水平上的致病作用目前尚不清楚。我们在此报告了 3 名 NF2 患者的 22q12 微缺失特征，他们具有不同的表型复杂性。通过对 22q12 拓扑关联域（TAD）和调控元件的计算机分析，以及对患者缺失侧翼的 12 个基因的表达分析，研究了位置的可能影响。在表型最轻者的患者中发现了一个 147 Kb 的微缺失，而另外两名患者则发现了一个 561 Kb 和一个 1.8 Mb 的大缺失，表现出更严重的症状。后两名患者表现出智力障碍，可能与 基因缺失有关。微缺失从一个到五个 TAD 变化，根据四个缺失侧翼基因的表达水平改变，包括 ，22q12 染色质调控景观可能与患者中最大缺失的早期缺血事件有关。我们的结果表明，确定缺失范围可以提供预后标志物，预测 NF2 表型，并为潜在的治疗靶点提供依据，从而全面改善患者的管理。
