The frequencies of very long-chain acyl-CoA dehydrogenase deficiency genetic variants in Japan have changed since the implementation of expanded newborn screening
The frequencies of very long-chain acyl-CoA dehydrogenase deficiency genetic variants in Japan have changed since the implementation of expanded newborn screening
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DOI：
10.1016/j.ymgme.2022.03.009
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发表时间：
2022-05-09
影响因子：
3.8
通讯作者：
Taketani, Takeshi
中科院分区：
文献类型：
--
作者：
Osawa, Yoshimitsu;Kobayashi, Hironori;Taketani, Takeshi
超长链酰基辅酶a脱氢酶（VLCAD）缺乏症已成为日本使用串联质谱法扩大新生儿筛查（ENBS）的目标。自ENBS实施以来，已经确定了许多导致VLCAD缺陷的新型ACADVL变体。在这项研究中，研究了日本VLCAD缺乏患者在ENBS前后的基因型差异。通过ENBS鉴定的61名受试者（ENBS组）和随后出现临床症状但未进行ENBS的40名患者（ENBS前期组）的ACADVL变异进行了比较。ENBS组的受试者进行基因检测和/或VLCAD酶活性测定。enbs前组患者被分为三种临床表型并进行基因检测。本研究发现，p.K264E、p.K382Q和c.996dupT变异在两组中均有发现，但其在ENBS组中的频率（分别为5.2%、3.1%和4.2%）低于ENBS前组（分别为16.5%、12.7%和10.1%）。此外，p.C607S、p.T409M、p.M478I、p.G289R、p.C237R、p.T260M、p.R229*在ENBS组中均有特异性表达。其中，p.C607S出现频率最高（18.8%）。p.C607S杂合的患者表现出7-42%的对照酶活性。p.C607S被怀疑是日本人特有的。根据酶活性的比较，p.C607S变异体患者可能比p.A416T、p.A180T、p.R450H和p.K264E变异体患者表现出更高的酶活性，而p.A416T、p.A180T、p.R450H和p.K264E变异体是导致该病肌病形式的原因。自日本ENBS开始以来，VLCAD缺陷基因型发生了变化。(c) 2022爱思唯尔公司版权所有。
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency has been a target of expanded newborn screening (ENBS) using tandem mass spectrometry in Japan. Since the implementation of ENBS, a number of novel ACADVL variants responsible for VLCAD deficiency have been identified. In this study, genotypic differences in Japanese patients with VLCAD deficiency were investigated before and after ENBS. The ACADVL variants in 61 subjects identified through ENBS (ENBS group) and in 40 patients who subsequently developed clinical symptoms without undergoing ENBS (pre-ENBS group) were compared. Subjects in the ENBS group underwent genetic testing and/or VLCAD enzyme activity measurements. Patients in the pre-ENBS group were stratified into three clinical phenotypes and underwent genetic testing. This study revealed that the variants p.K264E, p.K382Q and c.996dupT were found in both groups, but their frequencies were lower in the ENBS group (5.2%, 3.1% and 4.2%, respectively) than in the pre-ENBS group (16.5%, 12.7% and 10.1%, respectively). In addition, p.C607S, p.T409M, p.M478I, p.G289R, p.C237R, p.T260M, and p.R229* were exclusively identified in the ENBS group. Among these variants, p.C607S exhibited the highest frequency (18.8%). The patients who were heterozygous for p.C607S demonstrated 7-42% of control enzyme activity. p.C607S is suspected to be unique to Japanese individuals. According to a comparison of enzyme activity, patients with the p.C607S variant may exhibit higher enzyme activity than those with the p.A416T, p.A180T, p.R450H, and p.K264E variants, which are responsible for the myopathic form of the disease. The VLCAD deficiency genotypes have changed since the initiation of ENBS in Japan. (c) 2022 Elsevier Inc. All rights reserved.