CSF1R

Inheritance Pattern: AR

Disease ID:MONDO:0032772

Submitter: ClinGen

CSF1R was first reported in relation to autosomal recessive brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) in 2019 (PMID: 30982608, 30982609). The condition is characterized by early disease onset (<18 years old), developmental delay and/or cognitive decline, spasticity with abnormal reflexes and other pyramidal signs, parkinsonism, dysphagia, seizures, and speech disturbances. On radiographic imaging, patients typically present with diffuse osteosclerosis of the craniofacial bones (most prominent in the skull base), platyspondyly and sclerosis of the vertebral bodies, sclerotic pelvic bones, and tubular bones. MRI findings include progressive bilateral white matter lesions, calcifications, cerebral atrophy, ventriculomegaly, agenesis/thinning of the corpus callosum, Dandy-Walker malformation, and malformation of cortical development (PMID: 30982608, 30982609, 37349768). The CSF1R gene encodes the colony stimulating factor-1 receptor, which is a class III tyrosine kinase, and acts as a cell-surface receptor for CSF1 and IL-34 (PMID: 18467591). CSF1R is mainly expressed in the myeloid cells. The survival, proliferation, and differentiation of cells belonging to this lineage is maintained by CSF1R signaling (PMID: 24742461). Variants in CSF1R have also been reported individuals with the following disease entity: autosomal dominant hereditary diffuse leukoencephalopathy with spheroids [HDLS; also known as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)], which is characterised as an adult-onset disorder and includes behavioral, cognitive, and personality changes with progressive motor impairment +/- seizures or ataxia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, phenotypic variability, and potentially molecular mechanism for the gene CSF1R. Therefore, the following disease entities have been split into two disease entities: autosomal recessive CSF1R-related disorder (aka BANDDOS, OMIM: 164770) and autosomal dominant CSF1R-related disorders (aka HDLS/ALSP, OMIM: 221820). The split curation for autosomal dominant CSF1R-related disorder has been curated separately. This curation includes 9 probands with 9 distinct variants (missense, nonsense, insertion, in-frame deletion, frameshift, and splicing) across 6 publications (PMID: 30982609, 30282608, 33749994, 32464672, 37349768, 38934054). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The disease mechanism is believed to be loss of function. The gene-disease relationship is also supported by an animal model (PMID: 22046273) involving mice homozygous for a null mutation in the CSF1R gene, which recapitulated the microglial depletion and enlarged ventricles seen in affected individuals along with compressed parenchyma. A second knock-out mouse model (PMID: 11756160) was shown to recapitulate the skeletal phenotype, specifically osteopetrosis, seen in patients with biallelic CSF1R variants. Additional experimental evidence exists, but was not included in this curation as definitive status had been reached. In summary, there is definitive evidence supporting the relationship between CSF1R and autosomal recessive CSF1R-related disorder. This has been repeatedly demonstrated over time in both the research and clinical diagnostics settings, and has been upheld over time. This classification was approved by the Leukodystrophy and Leukoencephalopathy Working Group on April 21, 2026 (SOP Version #11).

Inheritance Pattern: AR

Disease ID:MONDO:0032772

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0009096

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0032772

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0800027

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0800027

Submitter: ClinGen

CSF1R was first reported in relation to autosomal dominant hereditary diffuse leukoencephalopathy with spheroids (HDLS) in 2011 (Rademakers et al., PMID: 22197934). HDLS (also known as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; ALSP) is a rare adult-onset disorder with onset typically in the fourth or fifth decade of life (mean age of onset: 40±10 years in females and 47±11 years in males). Symptoms and disease course are variable and can include behavioral, cognitive, and personality changes, progressive motor impairment (pyramidal and/or extrapyramidal), sometimes with ataxia or seizures. Most individuals show a rapid progression of disability and typically lose their ability to speak, perform voluntary movements, and eventually become unaware of their surroundings. At the late stage of disease, symptoms progress to a vegetative state with presence of primitive reflexes. AD CSF1R-related disorder is considered a primary gliopathy, and pathology is also notable for demyelination, axonal spheroids and reactive astrocytes. Of note, biallelic variants in CSF1R have been implicated in the autosomal recessive disorder BANDDOS which is characterized by brain abnormalities, progressive neurologic deterioration, and sclerotic bone dysplasia akin to dysosterosclerosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, phenotypic variability, and, potentially, molecular mechanism for the gene CSF1R. Therefore, the following disease entities have been split into two disease entities, autosomal recessive CSF1R-related disorder (aka BANDDOS, OMIM: 164770) and autosomal dominant CSF1R-related disorders (aka HDLS/ALSP, OMIM: 221820). The split curation for autosomal recessive CSF1R-related disorder has been curated separately. This curation includes 15 probands with 15 distinct variants (missense, splicing, and multi-exonic deletion) reported across two publications (PMIDs: 22197934, 39031193). Additional segregation analyses from a family from Rademakers et al., 2011 (PMID 22197934) was also included in the curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The disease mechanism has not been clearly delineated, but variant distribution and functional studies suggest altered tyrosine kinase activity and defective autophosphorylation of CSF1R as the potential mechanism (PMID 22197934, 24336230). This gene-disease relationship is also supported by an animal model (PMID: 25497733) involving a Csf1r heterozygous knock-out mouse, which recapitulates the neurological, behavioral, and pathological phenotype seen in humans. Additional experimental evidence exists, but was not included in this curation as definitive status had been reached. In summary, there is definitive evidence supporting the relationship between CSF1R and autosomal dominant CSF1R-related disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Leukodystrophy and Leukoencephalopathy Working Group on October 27, 2025 (SOP Version #11).

Inheritance Pattern: AD

Disease ID:MONDO:0009096

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0034143

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0009096

Submitter: Ambry Genetics