Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Abstract

Objective: To describe two novel heterozygous splicing variants of the CSF1R gene responsible for CSF1R-microglial encephalopathy in two unrelated Han Chinese families and further explore the relationship between the pathological and neuroimaging findings in this disease.Methods: The demographic data, detailed medical history, and clinical manifestations of two unrelated Han families with CSF1R-microglial encephalopathy were recorded. Some family members also underwent detailed neuropsychological evaluation, neuroimaging, and genetic testing. The probands underwent whole-exome sequencing (WES) or next-generation sequencing (NGS) to confirm the diagnosis. The findings were substantiated using Sanger sequencing, segregation analysis, and phenotypic reevaluation.Results: Both families presented with a dominant hereditary pattern. Five of 27 individuals (four generations) from the first family, including the proband and his sister, father, uncle, and grandmother, presented with cognitive impairments clinically during their respective lifetimes. Brain magnetic resonance imaging (MRI) depicted symmetric, confluent, and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The proband’s brother remained asymptomatic; brain MRI revealed minimal white matter changes, but pseudo-continuous arterial spin labeling (pCASL) demonstrated a marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum. Seven family members underwent WES, which identified a novel splice-site heterozygous mutation (c.2319+1C>A) in intron 20 of the CSF1R gene in four members. The proband from the second family presented with significant cognitive impairment and indifference; brain MRI depicted symmetric diffuse deep white matter changes and thinning of the corpus callosum. The proband’s mother reported herself to be asymptomatic, while neuropsychological evaluation suggested mild cognitive impairment, and brain MRI demonstrated abnormal signals in the bilateral deep white matter and corpus callosum. NGS of 55 genes related to hereditary leukodystrophy was performed for three members, which confirmed a novel splice-site heterozygous mutation (c.1858+5G>A) in intron 13 of the CSF1R gene in two members.Conclusions: Our study identified two novel splicing mutation sites in the CSF1R gene within two independent Chinese families with CSF1R-microglial encephalopathy, broadening the genetic spectrum of CSF1R-microglial encephalopathy and emphasizing the value of pCASL for early detection of this disease.

Primary microgliopathy presenting as degenerative dementias: A case series of novel gene mutations from India

“…This reported case series of 3 patients of CSF1R -related leukoencephalopathy or ALSP highlights the variability in the phenotypic presentation of CSF1R mutation: cases 3 and 5 presented with FTD and case 4 presented as atypical AD. Although a few Indian reports of dementia patients with CSF1R mutation are published, the genetic novelty in case 3 was pathogenic intronic 14 mutation and the clinical novelty was that aphasia was prominent in the course of illness [ 28 , 29 , 30 , 31 , 32 , 57 , 58 , 59 , 60 ]. Aphasia is described only in 19% of the series in literature [ 27 , 57 ].…”

“…Presently, a total of 115 C SF1R mutation sites have been identified worldwide in approximately 300 cases reported [ 57 , 58 , 59 , 60 ] and only 13 intronic pathogenic variants have been reported in the literature. Although several variants of CSF1R are implicated as a risk for AD, phenotypically atypical variant AD confirmed by the PET MR hypoperfusion pattern in case 4 is a rarity [ 16 ].…”

Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression

“…Recent discoveries indicate that genes associated with MS susceptibility are more frequently linked to microglial function than neurons or astrocytes, signifying a significant role for microglia in MS pathogenesis ( 274 ). However, mutations in the CSF1-receptor (CSF1R) gene, a pivotal microglial-specific gene associated with other leukoencephalopathies, have not been correlated with MS pathology, as no relevant mutations were identified in CSF1R sequencing studies of MS patients ( 275 – 278 ).…”