Novel mutations in ADSL for Adenylosuccinate Lyase Deficiency identified by the combination of Trio-WES and constantly updated guidelines.
Novel mutations in ADSL for Adenylosuccinate Lyase Deficiency identified by the combination of Trio-WES and constantly updated guidelines.
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通过 Trio-WES 和不断更新的指南相结合，发现 ADSL 腺苷酸琥珀酸裂解酶缺乏症的新突变
DOI：
10.1038/s41598-017-01637-z
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发表时间：
2017-05-09
影响因子：
4.6
通讯作者：
Guo J
中科院分区：
文献类型：
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作者：
Mao X;Li K;Tang B;Luo Y;Ding D;Zhao Y;Wang C;Zhou X;Liu Z;Zhang Y;Wang P;Xu Q;Sun Q;Xia K;Yan X;Jiang H;Lu S;Guo J
全外显子组测序（WES）是新一代测序技术（NGS）的一种，已成为鉴定外显子变异的有力工具。研究序列变异与人类疾病的因果关系成为NGS研究和临床应用的重要组成部分。最近，关于这些问题的重要准则已经公布，并将不断更新。本研究采用Trio-WES对两个临床诊断为“癫痫”的中国家系（包括先证者和未患病的父母）进行基因测序，并参照最新的指南对所鉴定的变异进行标准解释。最后，我们在两个中国家庭中鉴定了三个新的ADSL突变（c.71 C T，p.P24L; c.1387- 1389 delGAG，p.E463-; c.134 G A，p.W45*; NM_000026），并证实它们是ADSL疾病-腺苷酸琥珀酸裂解酶缺乏症的致病变体。在我们精细化的分子诊断后，以前报道的特异性治疗也被引入患者，但效果非常有限。总之，我们的研究证明了WES在探索人类疾病病因方面的能力和优势。使用不断更新的指南进行WES研究和解释序列变异是进行分子诊断和指导人类疾病个体化治疗的必要策略。
Whole-exome sequencing (WES), one of the next-generation sequencing (NGS), has become a powerful tool to identify exonic variants. Investigating causality of the sequence variants in human disease becomes an important part in NGS for the research and clinical applications. Recently, important guidelines on them have been published and will keep on updating. In our study, two Chinese families, with the clinical diagnosis of “Epilepsy”, which presented with seizures, psychomotor retardation, hypotonia and etc. features, were sequenced by Trio-WES (including the proband and the unaffected parents), and a standard interpretation of the identified variants was performed referring to the recently updated guidelines. Finally, we identified three novel mutations (c.71 C T, p.P24L; c.1387-1389delGAG, p.E463-; c.134 G A, p.W45*; NM_000026) in ADSL in the two Chinese families, and confirmed them as the causal variants to the disease-Adenylosuccinate Lyase Deficiency. Previous reported specific therapy was also introduced to the patients after our refined molecular diagnosis, however, the effect was very limited success. In summary, our study demonstrated the power and advantages of WES in exploring the etiology of human disease. Using the constantly updated guidelines to conduct the WES study and to interpret the sequence variants are a necessary strategy to make the molecular diagnosis and to guide the individualized treatment of human disease.