探讨DGKE基因变异致婴儿期非典型溶血尿毒综合征(aHUS)的临床表型及遗传学特征。

选择2021年6月西安市儿童医院收治的1例aHUS婴儿(患儿1)为研究对象。采用全外显子组测序(WES)筛选候选变异基因后，进行Sanger测序验证。根据人类基因突变数据库(HGMD，https：//www.hgmd.cf.ac.uk/)等生物信息学工具，了解DGKE基因变异是否为新发变异。根据美国医学遗传学与基因组学学会(ACMG)制定的《遗传变异分类标准与指南》(以下简称为"ACMG指南")，对检出的基因变异位点进行致病性评级。对变异位点进行氨基酸保守性分析和蛋白质建模功能分析，了解变异对临床表型的影响。以"DGKE""非典型溶血尿毒综合征""atypical hemolytic uremic syndrome"为中、英文关键词，在中国知网、万方数据知识服务平台、维普中文期刊服务平台及PubMed数据库中检索明确诊断为DGKE基因变异致aHUS患儿的相关文献。本次文献检索时限设定为2021年1月1日至2025年5月31日。本研究遵循的程序符合西安市儿童医院伦理委员会规定，并通过该伦理委员会审查及批准(伦理审批号：20250040)，并且征得患儿1监护人对本研究知情同意。

①患儿1为8个月龄女孩，以"腹泻伴肉眼血尿4 d"收入本院肾脏科治疗。患儿1的入院检查结果提示血尿、蛋白尿及血红蛋白(Hb)水平低，血小板计数(PLT)降低，乳酸脱氢酶(LDH)、尿素和肌酐水平升高，血清补体3、4水平正常。经血浆输注(PI)及血浆置换(PE)治疗后，对其随访4^＋年，患儿1的aHUS复发2次，尿蛋白持续呈阳性，肾功能正常。②WES结果显示，患儿1 DGKE基因第5外显子检出c.839A>T(p.D280V)纯合变异，其父亲和母亲无临床症状，均为该基因的杂合变异携带者，符合常染色体隐性遗传特征。该变异(c.839 A>T)为HGMD等数据库既往未见报道的变异。根据ACMG指南评级标准，该变异的致病性等级为意义不明确。多种生物信息学预测结果显示，该变异具有致病、有害和破坏性。DGKE蛋白三维结构建模结果显示，该蛋白变异产生异常的晶体结构和构象，可能导致其下游信号通路失调。③文献复习结果：根据本研究设定的文献检索策略，检索到国内外关于DGKE基因变异aHUS患儿研究的相关文献为7篇，共19例aHUS患儿，加上患儿1，共计20例aHUS患儿被纳入以下DGKE基因变异aHUS患儿临床表型及遗传学特征分析的结果如下。20例aHUS患儿中，男性患儿为16例，女性为4例，19例起病年龄<2岁；14例病程中伴蛋白尿，16例有肾病高血压，8例有不同程度补体水平降低，11例于随访期间复发1~2次；5例患儿于首次或复发期间死亡。

本研究发现DGKE基因c.839A>T(p.D280V)纯合变异为既往未见文献报道的新发变异，可导致婴儿期发生aHUS。DGKE基因变异相关aHUS婴儿常伴持续蛋白尿，具有较高复发风险。本研究结果拓展了DGKE基因变异谱，有助于提高临床医师对DGKE基因变异相关aHUS的认识与诊治水平。

To characterize the clinical phenotype and genetic features of infantile-onset atypical hemolytic uremic syndrome (aHUS) caused by DGKE gene variants.

One infant with aHUS (patient 1, the proband), admitted to Xi′an Children′s Hospital in June 2021, was investigated. Whole-exome sequencing (WES) was performed to identify candidate pathogenic variants, followed by validation using Sanger sequencing. Bioinformatics tools, including the Human Gene Mutation Database (HGMD, https: //www.hgmd.cf.ac.uk/), were used to determine whether the DGKE variant had been previously reported. The pathogenicity of the detected variant was classified according to the standards and guidelines for the interpretation of sequence variants issued by the American College of Medical Genetics and Genomics (ACMG). Amino acid conservation analysis and protein structural modeling were performed to evaluate the potential effect of the variant on protein structure and function, as well as its possible relevance to the clinical phenotype. A literature search was conducted using the keywords " DGKE" and " atypical hemolytic uremic syndrome" across CNKI, Wanfang Data, VIP, and PubMed databases, covering publications from January 1, 2021, to May 31, 2025. This study was approved by the Ethics Committee of Xi′an Children′s Hospital (Approval No. 20250040), and informed consent was obtained from the guardian of patient 1.

①Patient 1, an 8-month-old female, presented with a 4-day history of diarrhea and gross hematuria. Initial laboratory evaluations revealed hematuria, nephrotic-range proteinuria, decreased hemoglobin (Hb), thrombocytopenia, and elevated levels of lactate dehydrogenase (LDH), urea, and creatinine, with serum complement C3 and C4 levels within the normal range. The patient was treated with plasma infusion (PI) and plasma exchange (PE), and has been followed up for over 4 years. During this period, she experienced two relapses, with persistent proteinuria but preserved renal function. ② WES identified a homozygous variant in exon 5 of the DGKE gene [NM_003647.3: c.839A>T(p.D280V)], which has not been previously reported in HGMD. According to the rating criteria of the ACMG Guidelines, the variant was classified as a variant of uncertain significance. Both parents, who were asymptomatic, were confirmed to be heterozygous carriers, consistent with autosomal recessive inheritance. In silico analyses predicted this variant to be pathogenic. Three-dimensional modeling of the DGKE protein indicated that the mutation induces structural abnormalities, potentially disrupting downstream signaling pathways. ③ Literature review: According to the literature search strategy designed in this study, 7 relevant articles on DGKE gene variant-associated aHUS in children were retrieved from domestic and international sources, involving a total of 19 aHUS cases. Together with patient 1, a total of 20 aHUS children were included in the analysis of clinical phenotypes and genetic characteristics of aHUS children with DGKE gene variants. Among these, 16 were male and 4 female; 19 cases had disease onset before 2 years of age. Fourteen patients presented with nephrotic-range proteinuria, 16 developed hypertension, 8 exhibited varying degrees of complement depletion, and 11 experienced one or two relapses during follow-up. Five patients died during the initial episode or relapse.

This study identified that the homozygous variant c. 839A>T (p.D280V) in the DGKE gene is a previously unreported variant, which may cause infantile-onset aHUS, typically characterized by persistent proteinuria and a high risk of relapse. These findings expand the mutational spectrum of the DGKE gene and may enhance clinicians′ understanding, diagnosis, and management of DGKE-associated aHUS.