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We conducted a systematic screening of <jats:italic>SERPING1<\/jats:italic> 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\u2009+\u20093A\u2009&gt;\u2009C and c.686-7C\u2009&gt;\u2009G 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 <jats:italic>SERPING1<\/jats:italic> variant c.-21\u00a0T\u2009&gt;\u2009C in the <jats:italic>trans<\/jats:italic> 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\u2013phenotype correlations. Our findings also highlight the importance of comprehensive screening strategies and functional analyses in improving the C1-INH-HAE diagnosis and management.<\/jats:p>","DOI":"10.1007\/s10875-023-01565-w","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T03:24:12Z","timestamp":1692933852000},"page":"1974-1991","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort"],"prefix":"10.1007","volume":"43","author":[{"given":"Hana","family":"Grombirikova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor","family":"Bily","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Premysl","family":"Soucek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Kramarek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Hakl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Ballonova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbora","family":"Ravcukova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dita","family":"Ricna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Kozena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Kratochvilova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Sobotkova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radana","family":"Zachova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Kuklinek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavlina","family":"Kralickova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Krcmova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Hanzlikova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Vachova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Krystufkova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Dankova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milos","family":"Jesenak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Novackova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Svoboda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Litzman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6532-7053","authenticated-orcid":false,"given":"Tomas","family":"Freiberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"1565_CR1","doi-asserted-by":"publisher","unstructured":"Dewald G, Bork K. 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Therefore, no ethical approval was required.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"All participants gave their informed written consent for molecular genetic analysis of their samples. In addition, they provided written consent to collect and analyze their data.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Informed consent to publish their data was obtained from all individual participants included into the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"Authors RH and PK have received speaker and consultant honoraria from Shire and Takeda, and RH served as a principal investigator in the clinical trials supported by BioCryst Pharmaceuticals, Phavaris Netherands, Kalvista, Pharming, and CSL Behring. MaS has received speaker and consultant honoraria from Takeda, Pharming and Kalvista; travel support from CSL Behring and Takeda. RZ has received speaker, and consultant honoraria from CSL Behring and Takeda. MJ has received speaker and consultant honoraria from Takeda, Pharming, CSL Behring, Novartis, Zentiva, SOBI, ALK, Stallergenes-Greer, Chiesi, BerlinChemie Menarini and GSK; travel support from Company Novartis, Takeda, CSL Behring and ALK, and served as a principal investigator in the clinical trials supported by BioCryst Pharmaceuticals, Kalvista, Pharming, and Takeda. TF received speaker honoraria from Takeda. Authors HG, VB, PS, MK, LB, BR, DR, KK, LK, PK, IK, MV, OK, JH, ED, MN, MiS, and JL have no relevant financial or non-financial interests to disclose.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}]}}