CSF2RB was first reported in relation to autosomal recessive CSF2RB-related alveolar proteinosis in 2011 (Tanaka T, et al., PMID: 21075760). CSF2RB encodes the beta subunit of the granulocyte-macrophage colony-stimulating factor (GM-CSF) cell surface receptor and is involved in signaling pathways that are essential for surfactant clearance. Deficiency of CSF2RB results in alveolar macrophage dysfunction, which leads to impaired clearance and accumulation of surfactant in the alveoli and terminal bronchioles. This accumulation results in CSF2RB-related surfactant metabolism dysfunction, or pulmonary alveolar proteinosis, with various characteristics including ground-glass opacities with interlobular or intralobular septal thickening, resulting in a “crazy-paving” pattern on radiograph, enlarged foamy alveolar macrophages, dyspnea, and respiratory failure (Tanaka T, et al., PMID: 21075760). The age of onset for those presenting with isolated interstitial lung disease ranges from childhood to adulthood.
Four variants (2 frameshift, 1 nonsense, and 1 missense) that have been reported in 4 probands across 4 publications (PMIDs: 21075760, 21205713, 38259275, 38111540) are included in this curation. The mechanism of pathogenicity appears to be loss of function.
This gene-disease relationship is also supported by expression studies showing reduced or absent expression of beta chain (CSF2RB) in patients with PAP (PMID: 9410898), biochemical function assays demonstrating the role of signaling pathways in surfactant clearance (PMID: 21075760), animal models that recapitulate the human phenotype and a rescue of that phenotype with pulmonary macrophage transplantation (PMID: 25274301).
In summary, there is definitive evidence supporting the relationship between CSF2RB and autosomal recessive CSF2RB-related surfactant metabolism dysfunction. 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 ClinGen Interstitial Lung Diseases GCEP on the meeting date September 17, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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