CSF1R-Related Disorder: Prevalence of CSF1R Variants and Their Clinical Significance in the UK Population.

BACKGROUND AND

OBJECTIVES

CSF1R-related disorder (CSF1R-RD) is a devastating neurodegenerative disorder caused by variants in the colony stimulating factor-1 receptor (CSF1R) gene. CSF1R-RD leads to a variable combination of cognitive impairment, movement disorders, upper motor neuron signs, and spasticity with associated imaging abnormalities in brain white matter. Although increasingly recognized, there is evidence that it is significantly underdiagnosed or misdiagnosed, and its true prevalence is unknown. We leveraged the large data set of the UK Biobank to determine the prevalence of CSF1R mutations in the UK population and identify clinical phenotypes associated with these variants.

METHODS

Pathogenic and likely pathogenic CSF1R variants were identified in UK Biobank whole-exome sequencing data (N = 470,000). Medical history, including neurologic and psychiatric disease, were determined from self-reported and hospital collected codes, and the volume of MRI white matter hyperintensities were compared between variant carriers and controls.

RESULTS

We identified 25 individuals carrying 18 unique pathogenic variants and 107 individuals carrying 44 unique likely pathogenic variants-combined prevalence 132 (∼1 in 3,500). Pathogenic CSF1R variant carriers had increased risk of psychiatric disease (OR: 5.15, p = 0.0079), depression (OR: 10.52, p = 0.0015), and Parkinson disease (OR: 19.80, p = 0.0038). Using algorithmically defined diagnosis data, pathogenic or likely pathogenic variants (the combined group) carriers were at higher risk for both dementia (OR: 2.50, p = 0.046) and vascular dementia (OR: 4.72, p = 0.032).

DISCUSSION: Damaging variants in CSF1R are more common than expected in the general population and are associated with cognitive, psychiatric, and movement disorder diagnoses, which may reflect clinical manifestation of the disease. This study suggests that CSF1R-RD is either underreported, not diagnosed because of lack of genetic screening or that there is reduced penetrance.