SERPINE1 was first reported in relation to autosomal recessive complete plasminogen activator inhibitor 1 (PAI-1) deficiency in 1992 (Fay et al, PMID: 1435917), however partial PAI-1 deficiency was described in 1989 and 1991 (Schleef et al, PMID: 2496147; Dieval et al, PMID: 1899347). PAI-1 is encoded by SERPINE1, a serpin protease inhibitor. Complete plasminogen activator inhibitor 1 deficiency is characterized by moderate bleeding, however life-threatening bleeding events have been documented. Most commonly, bleeding is delayed after trauma or surgery; spontaneous bleeding does not occur. Evidence supporting this gene-disease curation includes case-level data, segregation data, and experimental data.
Summary of Case Level Data (9.0 points): Four unique variants have been reported in humans; three frame shift variants and a missense variant. Variants in this gene have been reported in at least 3 probands in 3 publications (PMID: 9207454; 21486382; 28229167; 32278876). Variants in this gene segregated with disease in 6 additional family members.
Summary of Segregation (LOD Score) (1.5 points): Using candidate gene sequencing, 7 affected individuals and 18 unaffected individuals from an Old Order Amish community were included in the LOD score (PMID: 1435917; 9207454).
Summary of Experimental Data (4 points): This gene disease relationship is supported by biochemical function (PMID: 1435917), Expression (PMID: 1435917), and model systems (PMID: 9529269) experiments.
In summary, SERPINE1 is definitively associated with autosomal recessive complete plasminogen activator inhibitor 1 (PAI-1) deficiency. This has been repeatedly demonstrated in both the research and the clinical diagnostic settings and has been upheld over time.
This gene-disease pair was originally approved by the HT GCEP in January of 2021. Subsequent curation was completed in October of 2023 using Gene-Disease Validity Standard Operating Procedures, Version 9.
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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