Marked intrafamilial phenotypic heterogeneity associated with the CSF1R c.2539G>A pathogenic variant in a Japanese family

Pathogenic variants in the colony-stimulating factor 1 receptor (CSF1R) gene cause CSF1R-related disorder (CSF1R-RD), which encompasses a broad phenotypic spectrum including a classical adult-onset leukoencephalopathy phenotype. Within this spectrum, considerable phenotypic heterogeneity has been increasingly recognized. The pathogenic missense variant c.2539G>A has been reported in a small number of patients with CSF1R-associated leukoencephalopathy; however, its associated clinical spectrum remains incompletely characterized. To characterize the clinical spectrum associated with the CSF1R c.2539G>A pathogenic variant in a Japanese family with CSF1R-RD. Clinical evaluations and genetic analyses, including whole-exome sequencing and Sanger sequencing, were performed in available family members. We detected the same heterozygous CSF1R c.2539G>A pathogenic variant in four members from a Japanese family. Two affected individuals presented with parkinsonism, cognitive decline, and white matter abnormalities typical of CSF1R-RD, whereas the other affected individual exhibited a phenotype consistent with typical Parkinson's disease (PD), without apparent cognitive impairment or radiological white matter abnormalities. The fourth individual initially had no overt neurological symptoms despite white matter changes on MRI and subsequently developed spastic gait with pyramidal signs, indicating intrafamilial phenotypic variability. These findings broaden the phenotypic spectrum associated with the CSF1R c.2539G>A pathogenic variant and highlight marked intrafamilial phenotypic heterogeneity, including a PD-like phenotype without typical cognitive or white matter abnormalities.