Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare and life-threatening condition characterized by recurrent localized edema. We conducted a systematic screening of SERPING1 defects in a cohort of 207 Czech patients from 85 families with C1-INH-HAE. Our workflow involved a combined strategy of sequencing extended to UTR and deep intronic regions, advanced in silico prediction tools, and mRNA-based functional assays. This approach allowed us to detect a causal variant in all families except one and to identify a total of 56 different variants, including 5 novel variants that are likely to be causal. We further investigated the functional impact of two splicing variants, namely c.550 + 3A > C and c.686-7C > G using minigene assays and RT-PCR mRNA analysis. Notably, our cohort showed a considerably higher proportion of detected splicing variants compared to other central European populations and the LOVD database. Moreover, our findings revealed a significant association between HAE type 1 missense variants and a delayed HAE onset when compared to null variants. We also observed a significant correlation between the presence of the SERPING1 variant c.-21 T > C in the trans position to causal variants and the frequency of attacks per year, disease onset, as well as Clinical severity score. Overall, our study provides new insights into the genetic landscape of C1-INH-HAE in the Czech population, including the identification of novel variants and a better understanding of genotype-phenotype correlations. Our findings also highlight the importance of comprehensive screening strategies and functional analyses in improving the C1-INH-HAE diagnosis and management.

Centre for Cardiovascular Surgery and Transplantation Brno Czech Republic

Department of Allergology and Clinical Immunology St Anne's University Hospital in Brno Brno Czech Republic

Department of Immunology 2nd Medical School Charles University and University Hospital Motol Prague Czech Republic

Department of Immunology and Allergology Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Department of Immunology and Allergology University Hospital Pilsen Pilsen Czech Republic

Faculty of Medicine Masaryk University Brno Czech Republic

Faculty of Science Masaryk University Brno Czech Republic

Immunia Prague Czech Republic

Institute of Biostatistics and Analyses Ltd Brno Czech Republic

Institute of Clinical Immunology and Allergy University Hospital Hradec Kralove Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove Czech Republic

Institute of Rheumatology and Department of Rheumatology 1st Faculty of Medicine Charles University Prague Czech Republic

National Centre for Hereditary Angioedema Department of Pediatrics Department of Pulmonology and Pathophysiology Department of Clinical Immunology and Allergology Comenius University in Bratislava Jessenius Faculty of Medicine University Teaching Hospital in Martin Martin Slovakia

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Complex analysis of the national Hereditary angioedema cohort in Slovakia - Identification of 12 novel variants in SERPING1 gene