Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy

Eis, Peggy S.; Bruno, Christopher D.; Richmond, Todd; Koralnik, Igor J.; Hanson, Barbara A.; Major, Eugene O.; Chow, Christina R.; Hendel-Chavez, Houria; Stankoff, Bruno; Grill, Jacques; Taoufik, Yassine; Hatchwell, Eli

doi:10.3389/fneur.2020.00186

Cited by 11 publications

(19 citation statements)

References 88 publications

(135 reference statements)

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“…Host genetic risk factors have also been identified; for example, individuals with the HLA-DRB1*0401 allele were found to have limited ability to mount robust antiviral responses 55 , and polymorphisms of the tumour suppressor protein p53 -a binding site of large tumour antigen that may modulate viral gene expression -can increase susceptibility 56 . More recently, use of whole-exome sequencing has identified 19 rare germ line PML risk variants that affect 17 genes related to immune function 57 . Determining how these host genetic factors influence susceptibility to PML will be of great interest and could offer opportunities for personalized pharmacovigilance strategies.…”

Section: Pathogenesis Of Pmlmentioning

confidence: 99%

Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease

2020

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Section: Pathogenesis Of Pmlmentioning

confidence: 99%

Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease

2020

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“…However, our results suggest that when the cellular response is impaired, the neutralizing response could come into play and have an important role in PML development and outcome. Furthermore, NAb measurement after PML onset could be a risk prediction parameter in addition to genetic susceptibility, with germline genetic risk variants having recently been identified [29]. In this work, our results help shed light on JCV compartmentalization during PML and suggest that there may be a better prognosis for patients who develop high NAb titers against their own strain, both in plasma and CSF.…”

Section: Discussionmentioning

confidence: 57%

Inadequate Immune Humoral Response against JC Virus in Progressive Multifocal Leukoencephalopathy Non-Survivors

Solis

Guffroy

Lersy³

et al. 2020

Viruses

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JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients. There is currently no effective specific antiviral treatment and PML management relies on immune restoration. Prognosis markers are crucially needed in this disease because of its high mortality rate. In this work, we investigated the compartmentalization of JCV strains as well as the humoral neutralizing response in various matrices to further understand the pathophysiology of PML and define markers of survival. Four patients were included, of which three died in the few months following PML onset. Cerebrospinal fluid (CSF) viral loads were the highest, with plasma samples having lower viral loads and urine samples being mostly negative. Whether at PML onset or during follow-up, neutralizing antibody (NAb) titers directed against the same autologous strain (genotype or mutant) were the highest in plasma, with CSF titers being on average 430-fold lower and urine titers 500-fold lower at the same timepoint. Plasma NAb titers against autologous genotype or mutant were lower in non-survivor patients, though no neutralization “blind spot” was observed. The surviving patient was followed up until nine months after PML onset and presented, at that time, an increase in neutralizing titers, from 38-fold against the autologous genotype to around 200-fold against PML mutants. Our results suggest that patients’ humoral neutralizing response against their autologous strain may play a role in PML outcome, with survivors developing high NAb titers in both plasma and CSF.

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“…We used the output from processed lpWGS data (method above) run through Gencove’s proprietary ancestry inference workflow [https://www.gencove.com/products, https://docs.gencove.com/main/data-analysis-configurations/#human]. This ancestry inference workflow has been increasingly adopted as a more accurate method for genotyping and inferring ancestry 59,60 . Using this pipeline, we derived the following genetic ancestry population groups: African (AFR), Admixed American (AMR), Ashkenazi…”

Section: Methodsmentioning

confidence: 99%

Real-world genetic screening with molecular ancestry supports comprehensive pan-ethnic carrier screening

Shewcraft

Higashi

Zhang

et al. 2022

Preprint

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We characterize the clinical utility and economic benefits of a comprehensive pan-ethnic carrier screening panel that spans 282 monogenic disease conditions in a large, diverse population of 397,540 reproductive health patients. For 142,049 of these patients, we were able to accurately estimate genetic ancestries across 7 major population groups. We examined individual carrier and at-risk carrier couple (ARCC) rates with respect to self-reported and genetic ancestries across ancestry-specific and pan-ethnic panels. Our results show that this comprehensive panel identified >10-times the ARCCs compared with a two-gene pan-ethnic panel and provided a substantial benefit over ancestry-specific screening panels across the major population groups. Finally, we generated a universal cost-of-care model across the monogenic disease conditions represented on the comprehensive pan-ethnic carrier screening panel to demonstrate potential healthcare savings in addition to the demonstrated clinical benefits that could be realized adopting this type of panel as standard of care for all.

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Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy

Abstract: ACKNOWLEDGMENTSWe are grateful to the PML patients that participated in this study and Edward B. Smith, III for bringing this high unmet need for PML risk prediction to our attention.

Cited by 11 publications

References 88 publications

Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease

Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease

Inadequate Immune Humoral Response against JC Virus in Progressive Multifocal Leukoencephalopathy Non-Survivors

Real-world genetic screening with molecular ancestry supports comprehensive pan-ethnic carrier screening

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