PB0711 - A novel homozygous KLKB1 missense variant causative of severe Prekallikrein deficiency.

Background: Prekallikrein deficiency is a rare autosomal disorder caused by variants in KLKB1. It is generally not associated with a bleeding phenotype so is probably under reported, usually detected incidentally following an abnormal coagulation screen. Detection of Prekallikrein deficiency, in the presence of a prolonged APTT, is beneficial as it gives definitive explanation excluding other potential causes.

Aims: Genetic confirmation of Prekallikrein deficiency and identification of causative variant.

Methods: A 52 year old woman with Primary Sjögren’s syndrome was referred for investigation of ‘unexplained bruising to limbs’. Coagulation assays were performed as standard on a Sysmex analyser. Prekallikrein was measured using an APTT-based factor assay, also on a Sysmex analyser. NGS analysis was performed for the R90 Bleeding and Platelet disorder panel. Analysis was performed using a Twist Bioscience custom design panel run on a NovaSeq and the data analysed using Congenica. Putative pathogenic variants were confirmed by Sanger sequencing.

Results: Initial coagulation studies showed a normal INR but raised APTT. This was initially considered to be ‘consistent with the presence of a lupus anticoagulant’. Factor analysis showed a severe Prekallikrein deficiency (PK < 1 IU/dL). NGS analysis showed her to be homozygous for a c.1739G>T; p.(Gly580Val) missense variant in KLKB1 that scores as ‘likely pathogenic’ using ACGS Guidelines.

Conclusion(s): The identification of the homozygous p.(Gly580Val) missense variant confirms a diagnosis of congenital Prekallikrein deficiency. This explains the prolonged APTT and excludes its being an inhibitory antibody effect, in a patient with an autoimmune condition. To date only 15 KLKB1 variants have been reported associated with Prekallikrein deficiency (HGMD Professional 2021.4), only 6 of which are missense variants. The identification of this novel missense variant adds to our knowledge of KLKB1 / Prekallikrein deficiency.