Objective: To characterize the clinical presentation, neuropathological findings, and functional consequences associated with the CSF1R p.Ile794Thr variant.

Background: CSF1R-related disorder (CSF1R-RD) is a rare, fatal autosomal dominant leukoencephalopathy caused by pathogenic variants in the CSF1R gene, which primarily affect microglial function. The c.2381T>C (p.Ile794Thr) variant located in exon 18 represents the most frequently reported pathogenic mutation worldwide.

Method: We conducted a retrospective analysis of seven patients from four families evaluated at Mayo Clinic Florida. Their clinical data were compared with 71 previously reported cases of CSF1R-RD carrying the p.Ile794Thr variant identified through a systematic literature search of PubMed, Embase, Web of Science, and Google Scholar through January 2026. Clinical variables analyzed included age at disease onset, presenting symptoms, disease duration, survival, and neuroimaging characteristics. Haplotype analysis was performed to investigate the possibility of a founder effect. For functional assessment, HEK293 cells were transfected with empty pcDNA3.1 plasmid, full-length wild-type CSF1R plasmid, or the p.Ile794Thr mutant plasmid. CSF1R phosphorylation at residues Y546, Y708, and Y723 was evaluated using western blot and normalized to total CSF1R levels.

Results: Parkinsonism was significantly more frequent in the Mayo Clinic Florida cohort compared with previously reported p.Ile794Thr cases (86% vs. 42%; p = 0.04). Haplotype analysis indicated that the mutation likely arose independently across multiple lineages rather than originating from a single founder, including one confirmed de novo case. Neuropathological evaluation revealed hallmark features of CSF1R-RD, including white matter degeneration, axonal spheroids, and pigmented glial cells. Functional assays demonstrated that the p.Ile794Thr mutation impaired CSF1R phosphorylation.

Conclusion: The CSF1R p.Ile794Thr variant is associated with a relatively consistent clinical phenotype across populations, although the prevalence of parkinsonian features may differ. The presence of this mutation across diverse haplotypes supports the hypothesis that exon 18 represents a mutational hotspot in the CSF1R gene.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-neuropathological-and-functional-analysis-of-the-most-prevalent-csf1r-pathogenic-variant-p-ile794thr/