An easy-to-use, updated, interactive database of 1692 variants in coagulation factor IX (FIX) offers detailed insight into hemophilia B, according to findings from a review published in the Journal of Thrombosis and Haemostasis.
Patients with hemophilia B exhibit deficiencies in coagulation FIX, which are associated with “genetic variants in the 33.5 kb F9 gene located at the distal end of the long arm of the X chromosome (Xq27.1).” Genetic variants observed in individuals with hemophilia B are linked with a wide array of molecular defects in the F9 gene, including missense, nonsense, and splice site variants, as well as more complex deletions and insertions that may generate a shift in the reading frame. Because more than 1500 distinct F9 variants have been identified to date, simple listings are no longer beneficial.
The revised database was compiled via utilization of the widely accepted sequence nomenclature of the Human Genome Variation Society (HGVS), with all of the variants represented by their systematic names. Because the format of the HGVS is recognized worldwide, the data can be interpreted universally.
Three types of searches were enabled by the database:
- Causative genetic variants of hemophilia B in the F9 gene
- Patient entries related to these genetic variants (ie, any subfeatures and clinical results)
- Experimental protein structures of FIXa in the Protein Data Bank
Additionally, the database included a pipeline that is predictive of structural alterations based on existing FIXa models.
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The current revised version of the FIX database incorporates 598 newly reported F9 variants, which are in addition to the 1113 variants in the 2013 version. These variants, which were based on 5358 patient records, are presented within the myPHPadmin database. The variants were trimmed further during curation, to remove any incorrect or redundant entries, thus yielding an overall total of 1692 F9 genetic variants. These variants, corresponding to 88% (406 of 461) of the FIX residues, now include 70 additional residues.
There were 1645 newly reported entries in the database, which denoted a 52% database growth in F9 variants and a 44% increase in patient entries. A total of 48 novel experimentally determined structures of human FIXa were incorporated into the database for reference, along with an AlphaFold structural model for full-length, uncleaved FIX.
The 1692 F9 genetic variants include the following:
- 945 unique point variants (individual nucleotide base change)
- 281 deletions (loss of ≥1 nucleotide)
- 63 insertions (gain of ≥1 nucleotide)
- 23 indels (combination of insertions and deletions)
- 22 duplications (copying of ≥1 nucleotide)
- 6 complex (combination of insertions, deletions, and substitutions)
- 352 polymorphisms (genetic variants occurring in >1% of the population)
Most of the FIX variants were point variants, with the percentage having decreased from 73% in 2013 to 56% in the updated version. In contrast, the proportion of polymorphisms increased from 5% in 2013 to 21% in the revised version.
The 764 unique mild severity variants in the mature protein with known phenotypes included the following:
- 9.7% (74 of 764) of quantitative type I variants
- 15.2% (116 of 764) of predominantly qualitative type II variants
- 75.1% (574 of 764) of unspecified variants
Inhibitors were associated with 2.8% (152 of 5328) of the cases of hemophilia B, which represented an increase of
93 cases from the prior database.
“The updated database will assist clinicians and researchers in assessing treatment for patients [with hemophilia B],” the researchers concluded.
Xu ZX, Spencer HJ, Harris VA, Perkins SJ. An updated interactive database for 1692 genetic variants in coagulation factor IX provides detailed insights into haemophilia B. J Thromb Haemost. Published online February 12, 2023. doi:10.1016/j.jtha.2023.02.005