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Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort

H. Grombirikova, V. Bily, P. Soucek, M. Kramarek, R. Hakl, L. Ballonova, B. Ravcukova, D. Ricna, K. Kozena, L. Kratochvilova, M. Sobotkova, R. Zachova, P. Kuklinek, P. Kralickova, I. Krcmova, J. Hanzlikova, M. Vachova, O. Krystufkova, E. Dankova,...

. 2023 ; 43 (8) : 1974-1991. [pub] 20230825

Jazyk angličtina Země Nizozemsko

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc24000878
E-zdroje Online Plný text

NLK ProQuest Central od 1997-01-01 do Před 1 rokem
Medline Complete (EBSCOhost) od 2010-01-01 do Před 1 rokem
Health & Medicine (ProQuest) od 1997-01-01 do Před 1 rokem
Public Health Database (ProQuest) od 1997-01-01 do Před 1 rokem

Odkazy

PubMed 37620742
DOI 10.1007/s10875-023-01565-w
Knihovny.cz E-zdroje

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.

Citace poskytuje Crossref.org

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$a Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare and life-threatening condition characterized by recurrent localized edema. We conducted a systematic screening of SERPING1 defects in a cohort of 207 Czech patients from 85 families with C1-INH-HAE. Our workflow involved a combined strategy of sequencing extended to UTR and deep intronic regions, advanced in silico prediction tools, and mRNA-based functional assays. This approach allowed us to detect a causal variant in all families except one and to identify a total of 56 different variants, including 5 novel variants that are likely to be causal. We further investigated the functional impact of two splicing variants, namely c.550 + 3A > C and c.686-7C > G using minigene assays and RT-PCR mRNA analysis. Notably, our cohort showed a considerably higher proportion of detected splicing variants compared to other central European populations and the LOVD database. Moreover, our findings revealed a significant association between HAE type 1 missense variants and a delayed HAE onset when compared to null variants. We also observed a significant correlation between the presence of the SERPING1 variant c.-21 T > C in the trans position to causal variants and the frequency of attacks per year, disease onset, as well as Clinical severity score. Overall, our study provides new insights into the genetic landscape of C1-INH-HAE in the Czech population, including the identification of novel variants and a better understanding of genotype-phenotype correlations. Our findings also highlight the importance of comprehensive screening strategies and functional analyses in improving the C1-INH-HAE diagnosis and management.
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$a Hakl, Roman $u Faculty of Medicine, Masaryk University, Brno, Czech Republic $u Department of Allergology and Clinical Immunology, St. Anne's University Hospital in Brno, Brno, Czech Republic
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$a Sobotkova, Marta $u Department of Immunology, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic
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$a Kuklinek, Pavel $u Faculty of Science, Masaryk University, Brno, Czech Republic
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$a Kralickova, Pavlina $u Institute of Clinical Immunology and Allergy, University Hospital Hradec Kralove, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
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$a Hanzlikova, Jana $u Department of Immunology and Allergology, University Hospital Pilsen, Pilsen, Czech Republic
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$a Vachova, Martina $u Department of Immunology and Allergology, University Hospital Pilsen, Pilsen, Czech Republic $u Department of Immunology and Allergology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
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$a Krystufkova, Olga $u Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
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$a Jesenak, Milos $u National Centre for Hereditary Angioedema, Department of Pediatrics, Department of Pulmonology and Pathophysiology, Department of Clinical Immunology and Allergology, Comenius University in Bratislava, Jessenius Faculty of Medicine, University Teaching Hospital in Martin, Martin, Slovakia
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$a Novackova, Martina $u Institute of Biostatistics and Analyses, Ltd., Brno, Czech Republic
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$a Litzman, Jiri $u Faculty of Medicine, Masaryk University, Brno, Czech Republic $u Department of Allergology and Clinical Immunology, St. Anne's University Hospital in Brno, Brno, Czech Republic
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