This study aimed to assess the prevalence of pathogenic and likely pathogenic CSF1R variants in the Mayo Clinic Tapestry cohort. 

Colony Stimulating Factor 1 Receptor-Related Disorder (CSF1R-RD) is a rare, progressive neurodegenerative condition characterized by personality changes, cognitive decline, and motor impairment. Due to significant clinical overlap with disorders such as frontotemporal dementia and multiple sclerosis, CSF1R-RD is frequently misdiagnosed. While traditional prevalence estimates range from 0.5 to 1.5 per 100,000 individuals, recent analysis of the British Brain Bank suggests the true prevalence of pathogenic or likely pathogenic CSF1R variants may be as high as 28.09 per 100,000. As potential therapies are being explored, a better understanding of the genetic landscape is critical. 

We analyzed rare CSF1R variants (MAF ≤0.1%, GQ ≥20, DP ≥10) among 98,091 participants in the Tapestry cohort using the Omics Data Explorer. Variants were annotated using the CAVA pipeline (v2.0.12) and referenced against ClinVar (v202407), HGMD (v2024_2), and dbNSFP (v4.1). Pathogenicity was assessed via the SAVI-PI pipeline and classified based on ACMG guidelines. 

A total of 27 individuals were identified with 22 distinct CSF1R variants classified as pathogenic or likely pathogenic. These included eight stop-gain, five frameshift, four essential splice site, four missense (including one near a splice site), and one synonymous variant near a splice site. Additionally, 116 individuals carried 38 variants of uncertain significance. 

Our findings support recent data suggesting that pathogenic CSF1R variants are more common than previously believed, reinforcing evidence from the British Brain Bank. These results highlight the underdiagnosis of CSF1R-RD and underscore the value of genomic screening for early detection and potential therapeutic intervention.