The relationship between F10 and congenital factor X deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of November, 2019. This association was made using case-level and experimental data. More than a 100 variants in this gene are reported in humans, ranging from deletions, duplications, nonsense, frameshift, missense and splicing variants. Congenital Factor X deficiency is characterized by a bleeding diathesis, diagnosed by a prolonged aPTT and PT and reduced Factor X activity levels. Mutations in F10 were first associated with this disease in humans as early as 1989 by Reddy et al. (PMID: 2790181).
Summary of Case Level Data (12 points): The association is seen in at least 14 probands in 7 publications (PMID: 30036279, 1985698, 10746568, 30507709, 2790181, 1939653, 22931370). 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 have been reported to be biallelic loss of function, although a number of individuals with heterozygous variants showing mild to moderate FX deficiency are reported in the literature (PMID: 10746568). Some of these occurrences are noted in the genetic evidence, but not scored.
Summary of Experimental Data (4.5 points): FX activates prothrombin to thrombin in the blood coagulation pathway (PMID: 3286010). Mouse models that have the F10 gene knocked out show embryonic and perinatal lethality (PMID: 27626380, 10739370, 18036190); however, the mouse model with a missense variant, FX Friuli recapitulates FX deficiency in humans. The evidence from the mouse models parallel that seen in humans, where a complete loss of FX activity has not been reported in any patients.
In summary, the F10-Congenital FX 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 Nov 27, 2019. (SOP Version 7)
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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