Barzilai University Medical Center

9 Research Day 2020 Barzilai University Medical Center 1 PHENOTYPING AND GENE-SEQUENCING OF A COHORT OF NORMAL C1-INH ANGIOEDEMA Avner Reshef 1 , Iris Leibovich 1 , Yael Laitman 2 , Eitan Friedman 2 1 Angioedema Research Center, Barzilai University Medical Center, Ashkelon, 2 Laboratory of Molecular Genetics, Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel Background In 2000 a new subset of angioedema patients was described by Bork et al. They exhibited clinical expressions similar to Hereditary Angioedema patients (HAE), but with normal C1inhibitor (C1- INH) level and function (Type III HAE). Hypothesis Mutations in coagulation Factor XII gene ( F12 , mapped on Chr. 5q35.3) were described in normal C1-INH patients, but the underlying pathophysiology is poorly understood. We sought to investigate a cohort of Israeli angioedema patients with recurrent swelling attacks, without hives and normal C4, antigenic and functional C1-INH. Objectives We aimed to sequence two known F12 gene mutations (Thr309Lys, Thr309Arg) that are located on Chr. 5, exon 9 and two other, new F12 mutations (duplication and deletion c.971del72 and c.892dup18). A 37-item questionnaire was developed to further characterize the phenotypic expressions of the angioedema in this group. Results From a study population of 59 pts (57 females, 2 males) 38 patients could be analyzed (36 females, 2 male). Mean age was 37.7±12.6ys, (range 16-60). DNA was extracted from whole blood by the Promega Wizard Genomic DNA Purification Kit. Mutations within exon 9 of the F12 gene were analyzed by agarose gel separation and direct Sanger sequencing. Clinical manifestations included angioedema attacks in various locations (i.e. face, limbs, abdomen), with some patients having more than 25 attacks per year. Mean age of onset of angioedema was 23.9±10.4ys (range 7-53). Only the F12 mutation Thr328Lys was found in 17 pts (44.7%, all females, mean age 20.5±4.0 ys, range 15-29). The F12 mutation was found in 10/10 of affected females from the same family, 2/2 from another family, and one from a third family. Conclusions This is the first phenotype analysis and genetic mapping of F12 in normal C1-INH in Israel. The study shows that 17/38 symptomatic patients could be classified as normal C1-INH angioedema with F12 mutation.