Introduction: The hyperinsulinemia-hyperammonemia syndrome (HIHA) is the second most common cause of congenital hyperinsulinism and is caused by activating heterozygous missense mutations in GLUD1. In the majority of HIHA cases, the GLUD1 mutation is found to be de novo. We have identified three patients in whom clinical evaluation was suggestive of HIHA but with negative mutation analysis in peripheral blood DNA for GLUD1 as well as other known HI genes. Methods: We performed next-generation sequencing (NGS) on peripheral blood DNA from two children with clinical features of HIHA in order to look for mosaic mutations in GLUD1. Pancreas tissue was also available in one of these cases for NGS. In addition, NGS was performed on peripheral blood DNA from a woman with a history of HI in infancy whose child had HIHA due to a presumed de novo GLUD1 mutation. Results: Mosaic GLUD1 mutations were identified in these three cases at percent mosaicism ranging from 2.7% to 10.4% in peripheral blood. In one case with pancreas tissue available, the mosaic GLUD1 mutation was present at 17.9% and 28.9% in different sections of pancreas. Two unique GLUD1 mutations were identified in these cases, both of which have been previously reported (c.1493c>t/p.Ser445Leu and c.820c>t/p.Arg221Cys). Conclusion: The results suggest that low-level mosaic mutations in known HI genes may be the underlying molecular mechanism in some children with HI who have negative genetic testing in peripheral blood DNA.


中文翻译：

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与高胰岛素血症高氨血症综合征相关的镶嵌 GLUD1 突变

简介：高胰岛素血症-高氨血症综合征 (HIHA) 是先天性高胰岛素血症的第二常见原因，由激活 GLUD1 杂合错义突变引起。在大多数 HIHA 病例中，GLUD1 突变被发现是从头发生的。我们已经确定了 3 名患者，其临床评估提示患有 HIHA，但外周血 DNA GLUD1 以及其他已知 HI 基因的突变分析呈阴性。方法：我们对两名具有 HIHA 临床特征的儿童的外周血 DNA 进行了新一代测序 (NGS)，以寻找 GLUD1 的嵌合突变。其中一例还提供了胰腺组织用于 NGS。此外，还对一名在婴儿期有 HI 病史的妇女的外周血 DNA 进行了 NGS，该妇女的孩子因推测的 GLUD1 新突变而患有 HIHA。结果：在这三例病例中，外周血中鉴定出嵌合 GLUD1 突变，嵌合百分比范围为 2.7% 至 10.4%。在一例具有可用胰腺组织的病例中，镶嵌 GLUD1 突变在胰腺的不同部分中分别占 17.9% 和 28.9%。在这些病例中发现了两种独特的 GLUD1 突变，这两种突变均已在之前报道过（c.1493c>t/p.Ser445Leu 和 c.820c>t/p.Arg221Cys）。结论：结果表明，已知 HI 基因中的低水平嵌合突变可能是一些外周血 DNA 基因检测阴性的 HI 儿童的潜在分子机制。