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