Hereditary angioedema (HAE) is a rare disease with autosomal dominant inheritance, characterized by recurrent episodes of swelling of face, extremities and larynx, and attacks of abdominal pain. In its classic form, the HAE is caused by mutations in SERPING1, the gene encoding C1 inhibitor (C1-INH), and results from the quantitative and/or qualitative deficiency of C1-INH (HAE-C1-INH). Mutations in F12 gene coding for coagulation factor XII (FXII) were described in subsets of patients with HAE and normal C1-INH (FXII-HAE). In both groups, excessive activation of the kininogen-kinin pathway, leading to increased production of bradykinin, appears to be the major mechanism of development of angioedema. A subgroup of patients with HAE has normal C1-INH without mutations in SERPING1 or F12 genes, designated as patients with unknown HAE (U-HAE). The main strategy for detection of SERPING1 and F12 variants has been Sanger sequencing. Next Generation Sequencing (NGS) has recently uncovered novel pathways in HAE by revealing mutations in genes other than SERPING1 and F12 in U-HAE patients. Recent reports of mutations in the genes coding for angiopoietin-1 and plasminogen highlight the importance of NGS strategy to expand knowledge on HAE and to identify novel targets for treatment. Our group has pioneered genetic research on HAE in Brazil. We have previously reported on a large family of C1-INH-HAE who presented a deletion of a Cytosine on exon 3 of SERPING1 gene c.351delC. Our ongoing study enrolled fifty-nine individuals, 32F/27M, aged 6 months to 53 years-old, belonging to 16 families with C1-INH-HAE. We have identified 16 different mutations in SERPING1 in these non-related families, and of those, 6 were novel and ten had been previously described. We have investigated whether the type of mutation would affect clinical features of HAE-C1-INH patients. Patients with HAE from our cohort were classified as carrying missense or non-missense mutations (nonsense, insertion/deletions, and duplication). There were no significant differences between the two groups regarding clinical severity scores, even after adjusting for gender and estrogen sensitivity. One of the most intriguing factors about HAE is the variability of clinical symptoms and severity among patients who share the same genetic mutation, and high variability of symptoms over time in the same patient. It is possible that environmental factors could play a role, however genotype-phenotype correlations need to be studied in more detail. In this regard, identification of genes which could modulate expression of disease could result in more effective patient-based management strategies. Therefore, the objectives of the project which will be conducted abroad are: to investigate genotype-phenotype correlations among patients with HAE due to C1 Inhibitor deficiency using whole exome sequencing; to use whole exome sequencing to identify novel genetic variants as cause of disease among patients with HAE with normal C1 Inhibitor and absence of SERPING1 and F12 gene mutations; and to gain expertise in analyzing next generation sequencing data in an international reference laboratory. In order to develop these studies, collaboration with Prof. Sven Cichon and his group has been established. Initially, genetic data will be obtained of members of a Brazilian family with a known SERPING1 mutation, identifying candidate mutations which may influence disease severity, and subsequently it is expected to follow-up the findings in a large cohort of Swiss patients/families with HAE. This will provide Mrs. Luana S. M. Maia with a great opportunity to gains expertise in molecular genetics and to improve the quality of her research. It is expected that the results of her studies under Prof. Cichon´s supervision will result in a PhD thesis of elevated scientific content, and in publications at scientific journals of high impact.
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