Colony-stimulating factor 2 receptor alpha (CSF2RA) was first reported in relation to pseudoautosomal recessive pulmonary alveolar proteinosis simultaneously by two research groups in 2008 (Martinez-Moczygemba et al., PMID: 18955567; Suzuki et. al., PMID: 18955570). CSF2RA is located in the pseudoautosomal region (PAR1) of the X and Y chromosomes and is associated with either biallelic or hemizygous (Turner syndrome) variation. CSF2RA is part of the receptor complex for the granulocyte-macrophage colony-stimulating factor (GM-CSF) which is involved in the signaling pathway responsible for alveolar macrophage development and function (PMID: 26324812). Alveolar macrophages are responsible for immune response, clearing debris, and surfactant turnover in the lungs. The accumulation of debris and lack of surfactant turnover leads to pulmonary alveolar proteinosis (PAP). PAP can develop as a result of autoantibodies to GM-CSF (>90% of cases) or to germline variation in the GM-CSF receptor complex. Characteristic features of disease can include but are not limited to: milky bronchoalveolar lavage fluid, crazy-paving pattern on radiograph, enlarged and foamy appearing macrophages, dyspnea, respiratory insufficiency, or cyanosis (PMID: 30846703). Age of onset for hereditary forms of PAP is apparently highly variable with a majority of cases in this curation presenting in late infancy or childhood. Six variants (missense, nonsense, canonical splice site, and frameshift deletion) that have been reported in six probands in 2 publications (PMIDs 20622029, 25425184) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by a mouse model that nearly fully recapitulates the human patient phenotype, expression studies, and rescue of function in patient iPSC cells transfected with wildtype CSF2RA (PMIDs: 20622029, 26484569, 35043685, 24279725). In summary, there is definitive evidence supporting the relationship between CSF2RA and pseudoautosomal recessive pulmonary alveolar proteinosis. 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 Disease GCEP on the meeting date September 16, 2025 (SOP Version 11).
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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