The relationship between F13A1 and Factor XIIIA deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of February, 2019. This association was made using case-level and experimental data. At least 25 pathogenic variants in this gene are reported in ClinVar, including nonsense, frameshift, missense and splicing variants. F13A1 encodes A subunits, which have catalytic function, of the coagulation factor XIII. FXIII is a transglutaminase that forms intramolecular gamma-glutamyl-epsilon-lysine crosslinking between fibrin molecules to stabilize blood clots. Factor XIIIA deficiency is characterized by a bleeding diathesis, poor wound healing and reduced Factor XIII activity levels. Mutations in F13A1 were first associated with this disease in humans as early as 1992 by Board et al. (PMID: 8324218) and Kamura et al (PMID: 1644910).
Summary of Case Level Data (12 points): The association is seen in at least 10 probands in 7 publications (PMID: 9531593, 1353995, 12100162, 1644910, 7727776, 8025280, 19438481). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.
The mechanism for disease is expected to be biallelic loss of function.
Summary of Experimental Data (4.5 points): Mouse models recapitulating FXIII deficiency and rescue using rFXIII have been reported (PMID: 12529747, 18224415).
In summary, the F13A1 - Factor XIIIA deficiency gene-disease relationship is definitive. 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 Hemostasis/Thrombosis GCEP on July 22, 2020. (SOP Version 6).
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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