Submission Details

PFN1 was first reported in relation to autosomal dominant ALS18 in 2012 (Wu et al, 2012; PMID: 22801503). At least 7 variants (all missense) with a possible association with ALS18 have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 12 probands with ALS in 6 publications (PMIDs: 22801503, 23141414, 23428184, 25499087, 31802421, 31401564). Variants in this gene have been found to segregate with disease in at least 17 additional family members. This gene-disease association is supported by animal models( PMIDs: 28040732, 27681617) and functional assays in patient (PMID: 31444357) and non-patient cells (PMIDs: 22801503, 26908597, 31444357). The mechanism for disease is currently unclear but is suspected to involve heterozygous toxic gain-of-function, a dominant-negative mechanism, or a loss-of-function mechanism, though the former appears most likely (Wu et al, 2012 - PMID: 22801503; Yang et al, 2016 - PMID: 27681617; Tanaka et al, 2016 - PMID: 26908597; Fil et al, 2017 - PMID: 28040732; Giampetruzzi et al, 2019 - PMID: 31444357). In summary, there is currently definitive evidence that has been replicated over time to support this gene-disease relationship, and no convincing contradictory evidence has emerged. Of note, one additional variant (a NMD- frameshift variant) has been reported in at least 3 reportedly unrelated families (though they may be distantly related) with autosomal dominant Paget disease of bone in 2 publications (Merlotti et al, 2020 - PMID 32392277; Scotto di Carlo et al, 2020 - PMID: 31991009). Due to the differences in apparent molecular mechanism and phenotype his gene-disease relationship was not assessed as part of the PFN1-ALS curation.