Pathogenic MUYTH and Novel H3F3A Variants in Glioblastoma: A Case Report and Literature Review (P4-5.005).

in Neurology by Ryan Rilinger, Christine Cordova, Andrew Dhawan

TLDR

  • Researchers report a novel somatic variant in the histone gene in a glioblastoma patient with a monoallelic pathogenic variant, supporting the hypothesized association between histone genes and glioblastoma.
  • Computational tools predicted deleterious effects for the variant, and a literature review identified a neighboring variant associated with glioma.
  • The study's findings highlight the importance of histone genes in glioblastoma and suggest potential therapeutic targets for this disease.

Abstract

We describe a novel somatic variant in the histonegene in a glioblastoma patient with monoallelicpathogenic variant. We computationally characterize this histone variant and review the literature for histone variants in patients withvariants and glioblastoma. Glioblastoma has a demonstrated association with inherited polyposis syndromes, including those due to biallelic pathogenic variants in. Moreover, there is an emerging understanding of the germline genetic background on which glioblastoma arises. For instance, somatic histone variants in glioblastoma have been hypothesized to co-occur in those with monoallelic germline variants in, but few cases have been reported. We report a case of a patient with glioblastoma and a presumed monoallelic germline pathogenic variant in, found on tumor genomic profiling to have a somaticvariant of uncertain significance (VUS). We characterized this variant using Variant Effects Predictor, PolyPhen-2, and SIFT, and reviewed literature relating to somatic histone variants in glioblastoma. A 66-year-old right-handed female presented with one year of right hemibody weakness, hypoesthesia, incoordination, and expressive aphasia. A left frontal mass was biopsied and found to be a glioblastoma, WHO Grade 4, IDH-wildtype, MGMT hypermethylated. Tumor genomic profiling revealed a pathogenic variant in(p.Y179C, variant allele frequency 49%) and a VUS in(p.R3C, variant allele frequency 23%). Her variant inhad not been previously characterized in glioblastoma. Mixed effects are predicted by computational tools: neutral impact with 65% certainty (PredictSNP2), likely pathogenic (FATHMM-XF), possibly damaging (Variant Effects Predictor, PolyPhen-2), and deleterious (low confidence, SIFT). Literature review identified a report of a neighboring variant,p.R2C, also predicted to associate with glioma. Our report augments the hypothesized association between monoallelic germline pathogenic variants inand histone variant glioblastoma, reporting a novel somaticvariant with putative deleterious effects.Mr. Rilinger has nothing to disclose. Dr. Dhawan has nothing to disclose.

Overview

  • The study reports a novel somatic variant in the histone gene found in a glioblastoma patient with a monoallelic pathogenic variant.
  • The researchers characterized the variant using computational tools and reviewed literature on somatic histone variants in glioblastoma.
  • The study aims to further understand the association between monoallelic germline pathogenic variants in histone genes and histone variant glioblastoma.

Comparative Analysis & Findings

  • The somatic variant in the histone gene was found to have a variant allele frequency of 49% and was predicted to have deleterious effects.
  • Computational tools predicted mixed effects for the variant, ranging from neutral to likely pathogenic.
  • A literature review identified a report of a neighboring variant, p.R2C, also predicted to associate with glioma.

Implications and Future Directions

  • The study's findings support the hypothesized association between monoallelic germline pathogenic variants in histone genes and histone variant glioblastoma.
  • Future research should investigate the role of histone variants in glioblastoma onset and progression.
  • The identification of novel somatic variants in histone genes may lead to the development of targeted therapies for glioblastoma treatment.
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