KLKB1

Inheritance Pattern: AR

Disease ID:MONDO:0012901

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012901

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012901

Submitter: ClinGen

KLKB1 gene encodes prekallikrein (PK), also called “Fletcher factor”, the zymogen of the serine protease plasma kallikrein, which participates in the initiation of the intrinsic pathway of coagulation together with factor XII (FXII), FXI and the non-enzymatic cofactor high-molecular weight kininogen (HMWK). Moreover PK mediates the inflammatory response by liberating the vasodilatory and proinflammatory nonapeptide bradykinin from HMWK. KLKB1 was first reported in relation to inherited prekallikrein deficiency in 2003 (Shigekiyo T et al, PMID: 12871337) in a 47 years old male in which prolongation of the aPTT was discovered during coagulation tests before surgery. He referred episodes of epistaxis. Plasma PK activity was about 1% and molecular analysis showed homozygosis for the p.Gly420Glu (p.Gly401Glu in the paper) variant in KLKB1. Heterozygous family members showed a normal aPTT but reduced (mean 38%) PK activity. No patients with bleeding were described so far, except one with epistaxis (PMID: 12871337). 11 variants have been reported in humans: 6 missense, 3 nonsense and 2 frameshift. Evidence supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (functional evidence of biochemical function and expression, functional alteration in non-patient cells, non-human model organisms that replicate the disease). Summary of Case Level Data: 8.35 POINTS Variants in this gene have been reported in at least 11 probands in 10 publications (PMIDs: 15461630, 14652634, 21415712, 17598838, 25075649, 34847617, 17413767, 32202057, 20301226, 12871337) leading to a score of 12 for genetic evidence. The mechanism for disease is homozygous loss of function. Summary of Experimental Data: 4 POINTS This gene-disease association is supported by evidences of Expression (A): This study demonstrateed that PK is present in plasma and associates with HMWK (PMID 1069308). Evidence of Biochemical function: PK-deficient plasma showed a diminished rate of kaolin-activable coagulation (i.e. contact phase or intrinsic coagulation, that was corrected by reconstitution with purified prekallikrein suggesting that kallikrein activates FXII (PMID: 11344577). Functional alteration: two amino acid substitutions found in a patient (Gly123Arg and Asn143Ser; Gly104Arg and Asn124Ser in the paper) in the apple domain 2 (A2) of KLKB1 were expressed in E. Coli cells. The authors analyzed the binding activity of HMWK with the recombinant A2 and found that the binding activity of mutant PK was significantly reduced as compared with the wild-type (PMID:17598838). The Asn143Ser will be later described to be a common variant (MAF 0.54). A mouse model knockout for KLKB1 showed significantly low levels of plasma PK and a significantly prolonged aPTT (PMID: 25339356). In summary, we found definitive association of KLKB1 with inherited PK deficiency. This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on 12/5/2022 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0012901

Submitter: PanelApp Australia