Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis
Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis
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DOI：
10.1212/wnl.0000000000001129
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发表时间：
2015-01-13
期刊：
影响因子：
9.9
通讯作者：
Evans, D. Gareth
中科院分区：
文献类型：
--
作者：
Smith, Miriam J.;Isidor, Bertand;Evans, D. Gareth
目的：我们的目的是确定我们的神经鞘瘤病队列中与 LZTR1 突变相关的个体的比例。方法：我们使用外显子组测序、桑格测序和拷贝数分析来筛选 65 名生殖系 NF2 或 SMARCB1 突变呈阴性的无关神经鞘瘤病个体。我们还筛选了 39 名单侧前庭神经鞘瘤 (UVS) 患者以及至少一种其他神经鞘瘤患者的样本，但这些患者没有可识别的种系或嵌合 NF2 突变。结果：我们在 16 名神经鞘瘤病患者中的 6 名 (37.5%) 中发现了种系 LZTR1 突变，这些患者至少有一名受影响的亲属，49 名散发患者中的 11 名 (22%) 以及我们队列中 39 名 UVS 患者中的 2 名。总共三名种系突变阳性患者出现了 UVS。通过对各 2 个肿瘤进行突变筛查，排除了 3 名没有 NF2、SMARCB1 或 LZTR1 种系突变的患者的嵌合现象。结论：我们的数据证实了 LZTR1 突变与神经鞘瘤病之间的关系。他们表明，LZTR1 种系突变会增加患前庭神经鞘瘤的风险，从而与 NF2 进一步重叠，并且神经鞘瘤病的进一步致病基因仍有待鉴定。
Objectives: We aimed to determine the proportion of individuals in our schwannomatosis cohort whose disease is associated with an LZTR1 mutation.Methods: We used exome sequencing, Sanger sequencing, and copy number analysis to screen 65 unrelated individuals with schwannomatosis who were negative for a germline NF2 or SMARCB1 mutation. We also screened samples from 39 patients with a unilateral vestibular schwannoma (UVS), plus at least one other schwannoma, but who did not have an identifiable germline or mosaic NF2 mutation.Results: We identified germline LZTR1 mutations in 6 of 16 patients (37.5%) with schwannomatosis who had at least one affected relative, 11 of 49 (22%) sporadic patients, and 2 of 39 patients with UVS in our cohort. Three germline mutation-positive patients in total had developed a UVS. Mosaicism was excluded in 3 patients without germline mutation in NF2, SMARCB1, or LZTR1 by mutation screening in 2 tumors from each.Conclusions: Our data confirm the relationship between mutations in LZTR1 and schwannomatosis. They indicate that germline mutations in LZTR1 confer an increased risk of vestibular schwannoma, providing further overlap with NF2, and that further causative genes for schwannomatosis remain to be identified.