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Genetic Factors in Rasmussen's Encephalitis Characterized by Whole-Exome Sequencing.

ABSTRACT: Rasmussen's encephalitis (RE) is a rare chronic neurological disorder characterized by unihemispheric brain atrophy and epileptic seizures. The mechanisms of RE are complex. Adaptive immunity, innate immunity and viral infection are all involved in the development of RE. However, there are few studies on the role of genetic factors in the mechanisms of RE. Thus, the objective of this study was to reveal the genetic factors in the mechanisms of RE. Whole-exome sequencing (WES) was performed in 15 RE patients. Ten patients with temporal lobe epilepsy (TLE), which is a common and frequently intractable seizure disorder, were used as the controls. Thirty-one non-silent single nucleotide variants (SNVs) affecting 16 genes were identified in the RE cases. The functions of the genes with SNVs were associated with antigen presentation, antiviral infection, epilepsy, schizophrenia and nerve cell regeneration. Genetic factors of RE were found first in this study. These results suggest that RE patients have congenital abnormalities in adaptive immunity and are susceptible to some harmful factors, which lead to polygenic abnormal disease.

SUBMITTER: Ai J

PROVIDER: S-EPMC8523672 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Genetic Factors in Rasmussen's Encephalitis Characterized by Whole-Exome Sequencing.

Ai Junhong J Wang Yisong Y Liu Dong D Fan Dongying D Wang Qiqi Q Li Tianfu T Luan Guoming G Wang Peigang P An Jing J

Frontiers in neuroscience 20211005

Rasmussen's encephalitis (RE) is a rare chronic neurological disorder characterized by unihemispheric brain atrophy and epileptic seizures. The mechanisms of RE are complex. Adaptive immunity, innate immunity and viral infection are all involved in the development of RE. However, there are few studies on the role of genetic factors in the mechanisms of RE. Thus, the objective of this study was to reveal the genetic factors in the mechanisms of RE. Whole-exome sequencing (WES) was performed in 15 ...[more]

PMID: 34675770

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Project description:BACKGROUND:Family studies have shown a strong heritability component for venous thromboembolism (VTE), but established genetic risk factors are present in only half of VTE patients. AIM:To identify genetic risk factors in two large families with unexplained hereditary VTE. METHODS:We performed whole exome sequencing in 10 affected relatives of two unrelated families with an unexplained tendency for VTE. We prioritized variants shared by all affected relatives from both families, and evaluated these in the remaining affected and unaffected individuals. We prioritized variants based on 3 different filter strategies: variants within candidate genes, rare variants across the exome, and SNPs present in patients with familial VTE and with low frequency in the general population. We used whole exome sequencing data available from 96 unrelated VTE cases with a positive family history of VTE from an affected sib study (the GIFT study) to identify additional carriers and compared the risk-allele frequencies with the general population. Variants found in only one individual were also retained for further analysis. Finally, we assessed the association of these variants with VTE in a population-based case-control study (the MEGA study) with 4,291 cases and 4,866 controls. RESULTS:Six variants remained as putative disease-risk candidates. These variants are located in 6 genes spread among 3 different loci: 2p21 (PLEKHH2 NM_172069:c.3105T>C, LRPPRC rs372371276, SRBD1 rs34959371), 5q35.2 (UNC5A NM_133369.2:c.1869+23C>A), and 17q25.1 (GPRC5C rs142232982, RAB37 rs556450784). In GIFT, additional carriers were identified only for the variants located in the 2p21 locus. In MEGA, additional carriers for several of these variants were identified in both cases and controls, without a difference in prevalence; no carrier of the UNC5A variant was present. CONCLUSION:Despite sequencing of several individuals from two thrombophilic families resulting in 6 candidate variants, we were unable to confirm their relevance as novel thrombophilic defects.

Project description:BackgroundThe etiology of Rasmussen's encephalitis (RE), a rare chronic neurological disorder characterized by CD8+ T cell infiltration and unihemispheric brain atrophy, is still unknown. Various human herpes viruses (HHVs) have been detected in RE brain, but their contribution to RE pathogenesis is unclear.MethodsHHVs infection and relevant immune response were compared among brain tissues from RE, temporal lobe epilepsy (TLE) and traumatic brain injury (TBI) patients. Viral antigen or genome, CD8+ T cells, microglia and innate immunity molecules were analyzed by immunohistochemical staining, DNA dot blot assay or immunofluorescence double staining. Cytokines were measured by multiplex flow cytometry. Cell apoptosis was visualized by TUNEL staining. Viral infection, immune response and the severity of unihemispheric atrophy were subjected to correlation analysis.ResultsAntigens of various HHVs were prevalent in RE and TLE brains, and the cumulative viral score of HHVs positively correlated with the unihemispheric atrophy in RE patients. CD8+ T cells infiltration were observed in both RE and TLE brains and showed co-localization with HHV antigens, but their activation, as revealed by Granzyme B (GZMB) release and apoptosis, was found only in RE. In comparison to TLE, RE brain tissues contained higher level of inflammatory cytokines, but the interferon-β level, which was negatively correlated with cumulative viral score, was relatively lower. In line with this, the DNA sensor STING and IFI16, rather than other innate immunity signaling molecules, were insufficiently activated in RE.ConclusionsCompared with TBI, both RE and TLE had prevalently HHV infection and immune response in brain tissues. However, in comparison to TLE, RE showed insufficient activation of antiviral innate immunity but overactivation of cytotoxic T cells. Our results show the relatively lower level of antiviral innate immunity and overactivation of cytotoxic T cells in RE cases upon HHV infection, the overactivated T cells might be a compensate to the innate immunity but the causative evidence is lack in our study and need more investigation in the future.

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Genetic Factors in Rasmussen's Encephalitis Characterized by Whole-Exome Sequencing.

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Genetic Factors in Rasmussen's Encephalitis Characterized by Whole-Exome Sequencing.

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