Molecular Genetics of Fletcher and Fitzgerald Traits

Deficiencies of the plasma protease zymogen prekallikrein (PK) and its substrate, high molecular weight kininogen (HK), were discovered in 1965 and 1975, respectively. Initially, they were referred to as Fletcher and Fitzgerald traits after the first patients identified. Shortly thereafter, other deficient subjects were discovered, such as Williams and Reid. Williams trait is a kininogen null plasma, whereas Fitzgerald trait contains low molecular weight kininogen but no HK coagulant activity. In 2003, Fitzgerald trait was found to have a small HK, missing domain 6. Its DNA was sequenced, and a deep intronic InDel of unknown significance in KNG1 was hypothesized to be causative. Due to technical progress and new scientific insights, we were now able to sequence and reevaluate cell-free DNA from these historic plasma samples using pyro- and next generation sequencing techniques. As a control, Williams plasma was confirmed to carry the homozygous KNG1 variant c.586C>T, p.Arg196*. Fletcher trait was found to be KLKB1 c.451dupT (rs560588447), the most prevalent African variant, leading to PK deficiency. Fitzgerald and Reid traits were found to have the same variant, c.1609_1610delCA p.Gln537Aspfs*25 (rs758429575), in KNG1s exon 10. This variant likewise only occurs in people of African descent, which is consistent with Reid's and Fitzgerald's reported ancestry. On immunoblots, Fitzgerald and Reid plasmas show a small HK with antibodies to HK's domain 5, but none with antibodies to domain 6, rendering the present frameshift mutation solely responsible for the residual HK in Fitzgerald trait. Thus, the first cases of PK and HK deficiency discovered have now been genetically clarified. They confirm that no missense mutations are currently known to cause HK deficiency. Further, they emphasize the comparatively increased prevalence of PK and HK deficiency in sub-Saharan Africans. This finding suggests that widespread diseases may have influenced progression of these mutations in this population.

McCrae:Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lämmle:Takeda: Consultancy, Other: Data Monitoring Committees for studies with rADAMTS13 in cTTP and acquired TTP; Sanofi: Other: Data Monitoring Committee, Mayari Study.