Medical Genetics Unit Polyclinic Sant'Orsola-Malpighi University Hospital Bologna Italy.
IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy.
Ann Clin Transl Neurol. 2019 Feb 25;6(3):475-485. doi: 10.1002/acn3.722. eCollection 2019 Mar.
We investigated the contribution to sporadic focal epilepsies (FE) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (mTOR)complex 1 (mTORC1).
We collected genetic data of 121 Italian isolated FE cases and 512 controls by Whole Exome Sequencing (WES) and single-molecule Molecular Inversion Probes (smMIPs) targeting 10 genes of the GATOR1, GATOR2, and TSC complexes. We collapsed "qualifying" variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls.
We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients ( = 0.006; exact unconditional test, one-tailed). Pathogenic variants were identified in and both major genes for Mendelian FE syndromes.
Our findings support the contribution of ultrarare variants in genes in the mTOR pathway complexes GATOR and TSC to the risk of sporadic FE and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause.
我们研究了编码调节机械靶蛋白（mTOR）复合物 1（mTORC1）组件的基因中的超罕见变异对散发性局灶性癫痫（FE）的贡献。
我们通过全外显子组测序（WES）和针对 GATOR1、GATOR2 和 TSC 复合物的 10 个基因的单分子分子反转探针（smMIPs）收集了 121 例意大利孤立性 FE 病例和 512 例对照的遗传数据。我们对跨检查基因的“合格”变异（超罕见且预测为有害或丧失功能）进行了汇总，并试图确定它们在病例与对照中的富集情况。
我们在病例中发现了 8 个合格变异，在对照中发现了 9 个，表明 FE 患者中存在变异富集（= 0.006；确切的无条件检验，单侧）。在 和 这两个主要的孟德尔 FE 综合征基因中都发现了致病性变异。
我们的研究结果支持 mTOR 途径复合物 GATOR 和 TSC 中的超罕见变异基因对散发性 FE 风险的贡献，以及罕见和常见癫痫之间的共同遗传基础。在最常见于临床实践中的孤立病例中发现单基因病因，可能为更广泛的患者群体提供了针对潜在遗传原因的精准治疗的前景。
