Novel c.2654+1G>A mutation in the CSF1R gene in a family with CSF1R‐microglial encephalopathy

Abstract

AbstractBackgroundThe colony‐stimulating factor‐1 receptor (CSF1R) is a transmembrane tyrosine kinase receptor that is mainly expressed in the brain‐resident microglia. Thus, microglial dysfunction due to CSF1R mutation may play a primary and pivotal role in the pathogenesis of CSF1R‐microglial encephalopathy. Neither the functional consequences of all known CSF1R mutations nor the full genetic spectrum of mutations causing CSF1R‐microglial encephalopathy have been fully elucidated. We aimed to describe a novel heterozygous splicing variant of the CSF1R gene that caused CSF1R‐microglial encephalopathy in a Han Chinese family.MethodThe demographic data, detailed medical history, and clinical manifestations were collected from a family with CSF1R‐microglial encephalopathy. Some family members also underwent neuropsychological evaluation, structural and functional magnetic resonance imaging (MRI), and whole‐exome sequence analyses.ResultFour generations of this family, including 27 members, presented with a medical history of a dominant hereditary pattern (Figure 1). Seven of these 27 individuals had died, while five presented with similar cognitive impairments clinically, including the proband, and his sister, father, uncle, and grandmother during their life. Brain MRI of the proband (Figure 2) and his sister (Figure 3) depicted symmetric confluent and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The brother of the proband remained asymptomatic, and the structural brain MRI only revealed minimal white matter changes; however, pseudo‐continuous arterial spin labeling (pCASL) demonstrated marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum (Figure 4). Whole‐exome sequencing was performed for seven family members, which identified a novel splice‐site heterozygous mutation (c.2319+1C>A) in intron 20 of the CSF1R gene in four members (Figure 5).ConclusionWe identified a novel splicing mutation (c.2319+1C>A) in intron 20 of CSF1R as the cause of CSF1R‐microglial encephalopathy in a Han Chinese family, which broadens the genetic spectrum of CSF1R‐microglial encephalopathy. We opine that clinically feasible pCASL techniques may be more sensitive to the alterations in CBF of associated with microglial density and cellular changes. This study highlights the potential value of pCASL techniques to improve the clinical diagnostic accuracy of CSF1R‐microglial encephalopathy.