Genotype-phenotype correlations in Brazilian patients with hereditary angioedema due to C1 inhibitor deficiency

Author(s)

Luana Sella Motta Maia

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2019-10-03

Examining board members

Luisa Karla de Paula Arruda; Fabio Fernandes Morato Castro; Herberto Jose Chong Neto

• Advisor: Luisa Karla de Paula Arruda; Adriana Santos Moreno

Abstract

Background Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is characterized by recurrent episodes of angioedema of the subcutaneous tissue and the gastrointestinal and respiratory tract. Our objective was to identify mutations in the SERPING1 gene, which codes for C1-INH, and to investigate the impact of the mutation type on the clinical characteristics of patients with A C1-INH-HAE. In addition, we investigated the ancestry in patients with normal C1-INH-HAE with mutations in the gene encoding coagulation factor XII, designated as AEH-FXII. Methods: SERPING1 analysis was performed on 205 individuals from 16 families of C1-INH-HAE index patients. Clinical data were collected during medical interviews. Genomic DNA was isolated from whole blood and PCR was performed with specific primers. Predicted functional analysis of mutations was performed using the bioinformatics tools SIFT, PolyPhen2 and MutationTaster. Disease severity was assessed by two independent scores. Patients were classified as having deletions, insertion, duplication, nonsense mutation and mutations affecting Arg466 in the reactive center (group 1, n = 48); and missense mutations, except those of Arg466 (group 2, n = 12). Ancestry analysis of the dominant mutation found in patients with AEH-FXII, c.983C> A (p.Thr328Lys), was performed on 6 patients with AEH-FXII and their parents (being a carrier of the mutation) evaluating previously described multiple subjects Europeans. Results: Sixty patients (33F: 27M), aged 10 months to 63 years, presented mutations in SERPING1. Fiftyeight had HAE-1 and two had HAE-2. SERPING1 mutations included 10 missense and 6 non-missense mutations (structural mutations leading to frameshifts or nonssense mutations), six of which were new. No significant differences were observed between patients in groups 1 and 2 regarding age, gender, estrogen sensitivity, age at onset of symptoms, angioedema presentation sites, need for long-term prophylaxis, and clinical severity scores. Conclusions: The present results showed that a variety of mutations lead to heterogeneous clinical manifestations of C1-INH-HAE and that the severity of the disease may not be closely related to the type of mutation. AEH-FXII patients were found to have the same pattern of Europeans\' multiple subjects, suggesting that this mutation has the same common European founder. (AU)

• FAPESP's process: 14/26693-5 - Hereditary Angioedema due to C1 inhibitor deficiency: characterization of mutations on SERPING1 gene, clinical correlations and investigation of ancestry
• Grantee: Luana Sella Motta Maia
• Support Opportunities: Scholarships in Brazil - Doctorate