Genetic screening for CSF1R variants in patients with dementia, parkinsonism, and multiple sclerosis

To determine the frequency of colony-stimulating factor 1 receptor gene (CSF1R) variants in a cohort of Mayo Clinic patients with different neurodegenerative disorders.

Blood samples collected from patients diagnosed in the past five years with early-onset (18-60 years) cognitive impairment, atypical parkinsonism and primary progressive multiple sclerosis (PPMS) were screened for variants in the CSF1R gene using Sanger sequencing. For individuals with CSF1R variants, clinical data were analyzed. An online tool, SIFT (https://sift.bii.a-star.edu.sg/), was applied to predict possible impact of CSF1R variants. Moreover, the identified CSF1R variants were expressed in HEK293 cells, and their effects on CSF1R phosphorylation were assessed by western blotting.

Samples from 310 patients with dementia (n = 135), PPMS (n = 96) and atypical parkinsonism (n = 79) were analyzed. Two novel CSF1R variants in the heterozygous state were identified: p.G872V (c.2615G > T) in a 60-year-old male with atypical parkinsonism and moderate microangiopathic leukoencephalopathy on MRI and p.K864Q (c.2590A > C) in a 45-year-old female with behavioral variant of frontotemporal lobar degeneration with extensive tau pathology who died by suicide. The latter patient was also a carrier of a MAPT gene mutation: p.N279K; c.837T > G. SIFT analysis predicted both CSF1R variants to be deleterious. Both patients had a positive family history for dementia. In vitro studies confirmed that both CSF1R p.K864Q and p.G872V variants disturbed CSF1R phosphorylation with a stronger effect for CSF1R p.G872V.

CSF1R-related disorder (RD) is often mis- and underdiagnosed. Genetic testing for CSF1R-RD should be applied more often in cases of early-onset neurodegenerative disorders with a combination of cognitive, psychiatric, and motor symptoms and a positive family history.