Search

Background: The biochemical and genetic characteristics of four very-long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD) patients, clarifying their pathogenic genetic factors and evaluating the application value of genetic diagnosis in the early diagnosis of VLCADD, are reported and discussed in this article.Methods: Patients underwent blood tandem mass spectrometry (MS/MS), urine gas chromatography (GC/MS), and high-throughput sequencing technology. New variants were analyzed for pathogenicity using bioinformatics software. Swiss-PdbViewer software was used to predict the effect of variants on the structure of the very-long-chain acyl-CoA dehydrogenase (VLCAD) protein.Result: A total of four VLCADD patients were diagnosed. They revealed elevated levels of C14, C14:1, C14:2, C14:1/C2, C14:1/C10, and C14:1/C12:1. Two patients were early-onset neonatal cases and died during infancy and the neonatal period, respectively. Seven kinds of variants were detected, including four novel variants. Bioinformatics software revealed that the variants were harmful, and the Swiss-PdbViewer results suggest that variation affects protein conformation.Conclusion: This study identified four novel ACADVL gene variants. These findings contribute to the understanding of the genetic basis and pathogenesis of VLCADD. Meanwhile, the study enriches the genetic mutation spectrum and the correlation between genotypes and phenotypes of VLCADD, indicating that genetic diagnosis plays an essential role in the early diagnosis and treatment of VLCADD.

Abstract Peripheral T‐cell lymphoma (PTCL) is a highly heterogeneous group of mature T‐cell malignancies. The efficacy of current first‐line treatment is dismal, and novel agents are urgently needed to improve patient outcomes. A close association between the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway and tumor promotion exists, revealing prospective therapeutic targets. This study, investigates the role of the cGAS‐STING pathway and its underlying mechanisms in PTCL progression. Single‐cell RNA sequencing showes that the cGAS‐STING pathway is highly expressed and closely associated with PTCL proliferation. cGAS inhibition suppresses tumor growth and impaires DNA damage repair. Moreover, Cdc2‐like kinase 1 (CLK1) is critical for residual tumor cell survival after treatment with cGAS inhibitors, and CLK1 suppression enhances sensitivity to cGAS inhibitors. Single‐cell dynamic transcriptomic analysis indicates reduced proliferation‐associated nascent RNAs as the underlying mechanism. In first‐line therapy, chemotherapy‐triggered DNA damage activates the cGAS‐STING pathway, and cGAS inhibitors can synergize with chemotherapeutic agents to kill tumors. The cGAS‐STING pathway is oncogenic in PTCL, whereas targeting cGAS suppresses tumor growth, and CLK1 may be a sensitivity indicator for cGAS inhibitors. These findings provide a theoretical foundation for optimizing therapeutic strategies for PTCL, especially in patients with relapsed/refractory disease.