Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia caused by small vessel thrombosis, thrombocytopenia, and renal failure. The common cause of aHUS is a dysregulation in the alternative complement pathway. Mutations in none complement genes such as diacylglycerol kinase epsilon (DGKE) can also result in this syndrome. Here, we report on a 19-year-old female with the clinical diagnosis of aHUS, who has unaffected consanguineous parents and an older sibling who was deceased from aHUS when she was seven months old. We performed whole exome sequencing (WES) followed by evaluation of detected variants for functional significance, using several online prediction tools. Next, in order to confirm the detected pathogenic variant in proband and segregation analysis in her family, Sanger sequencing was done. The novel variant was analyzed in terms of its impact on the protein 3-dimensional structure by computational structural modeling. The results revealed that the proband carried a novel homozygous missense variant in DGKE located in exon 6 of the gene (NM_003647.3, c.942C > G [p.Asn314Lys]), and in silico analysis anticipated it as damaging. Protein computational study confirmed the influence of potential pathogenic variant on structural stability and protein function. We suggest that some variations in the catalytic domain of DGKE like p.Asn314Lys which can cause alterations in secondary and 3-D structure of protein, might lead to aHUS.

中文翻译：

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全外显子组测序揭示了 DGKE 催化结构域中的一种新的纯合变体：家族性溶血性尿毒症综合征的病例报告。

非典型溶血性尿毒症综合征（aHUS）是一种以小血管血栓形成、血小板减少和肾功能衰竭引起的微血管病性溶血性贫血为特征的罕见疾病。aHUS 的常见原因是替代补体途径的失调。非补体基因如二酰基甘油激酶ε (DGKE) 的突变也可导致这种综合征。在这里，我们报告了一名临床诊断为 aHUS 的 19 岁女性，她有未受影响的近亲父母和一个在她 7 个月大时死于 aHUS 的哥哥姐姐。我们使用几种在线预测工具进行了全外显子组测序 (WES)，然后评估检测到的变异的功能意义。接下来，为了确认在她家的先证者和分离分析中检测到的致病变异，完成了桑格测序。通过计算结构建模，分析了新变体对蛋白质 3 维结构的影响。结果显示，先证者在 DGKE 中携带一个新的纯合错义变体，位于基因的第 6 外显子 (NM_003647.3, c.942C > G [p.Asn314Lys])，并且计算机分析预计它具有破坏性。蛋白质计算研究证实了潜在致病变异对结构稳定性和蛋白质功能的影响。我们认为 DGKE 催化结构域的一些变化，如 p.Asn314Lys，可能导致蛋白质二级和 3-D 结构的改变，可能导致 aHUS。结果显示，先证者在 DGKE 中携带一个新的纯合错义变体，位于基因的第 6 外显子 (NM_003647.3, c.942C > G [p.Asn314Lys])，并且计算机分析预计它具有破坏性。蛋白质计算研究证实了潜在致病变异对结构稳定性和蛋白质功能的影响。我们认为 DGKE 催化结构域的一些变化，如 p.Asn314Lys，可能导致蛋白质二级和 3-D 结构的改变，可能导致 aHUS。结果显示，先证者在 DGKE 中携带一个新的纯合错义变体，位于基因的第 6 外显子 (NM_003647.3, c.942C > G [p.Asn314Lys])，并且计算机分析预计它具有破坏性。蛋白质计算研究证实了潜在致病变异对结构稳定性和蛋白质功能的影响。我们认为 DGKE 催化结构域的一些变化，如 p.Asn314Lys，可能导致蛋白质二级和 3-D 结构的改变，可能导致 aHUS。