FN1 was first reported in relation to autosomal dominant spondylometaphyseal dysplasia, corner fracture type (SMDCF) in 2017 (Lee et al., PMID: 29100092). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found clear differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities: autosomal dominant SMDCF (OMIM: 184255) and autosomal dominant glomerulopathy with fibronectin deposits 2 (GFND2; OMIM: 601894). The split curation for GFND2 has been curated separately. 12 variants (missense, in-frame deletion) that have been reported in at least 18 probands in 4 publications (PMIDs: 29100092, 30599297, 33605604, 37940834) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be haploinsufficiency. This gene-disease relationship is also supported by experimental evidence (expression-level evidence; PMIDs: 32561820). Altered expression of FN1 in mice impacted expression of osteoblastic markers. In summary, there is definitive evidence supporting the relationship between FN1 and autosomal dominant SMDCF. 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 Skeletal Disorders GCEP on the meeting date 3/6/2024 (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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