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HAE is characterized by recurrent self-limiting episodes of subcutaneous and submucosal edema that can be life-threatening when the upper airway is involved. Diagnostic delays and misdiagnoses are common due to the clinical overlap with allergic and histamine-mediated angioedema. Identification and functional characterization of novel\n                      <jats:italic>SERPING1<\/jats:italic>\n                      variants is essential for refining the mutational spectrum of this disease, enhancing molecular diagnostics, and guiding individualized therapeutic strategies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A 31-year-old female with a ten-year history of recurrent angioedema was diagnosed with HAE type I based on reduced serum C4, C1-INH antigen levels, and C1-INH functional activity. Sanger sequencing of the\n                      <jats:italic>SERPING1<\/jats:italic>\n                      gene was performed to identify the causative variant. Functional characterization of the identified splice-site variant was conducted using reverse transcription-PCR (RT-PCR) on patient-derived peripheral blood RNA and an in vitro minigene splicing assay in HEK293T cells. A retrospective analysis of seven HAE patients was performed, including clinical characterization, laboratory profiling, genetic analysis, and treatment outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A novel heterozygous splice-site variant, c.1029\u2009+\u20092T\u2009&gt;\u2009A, was identified at the canonical splice donor site of intron 6 of\n                      <jats:italic>SERPING1<\/jats:italic>\n                      . RT-PCR revealed reduced wild-type transcript expression and an aberrant transcript resulting from complete exon 6 skipping (c.890_1029del), predicted to cause a frameshift and premature termination codon (p.Ala297Glyfs*25). The minigene assay confirmed that the mutant construct produced no detectable canonical transcript; instead, three aberrant splice isoforms were identified, with exon 6 skipping as the predominant event. Long-term prophylactic treatment with Lanadelumab (300\u00a0mg subcutaneously every two weeks) achieved zero breakthrough attacks over a six-month follow-up period. In the retrospective cohort of seven patients, six were classified as type I and one as type II HAE. Seven distinct variants of the\n                      <jats:italic>SERPING1<\/jats:italic>\n                      gene were identified. Among these patients, five received long-term prophylaxis with Lanadelumab, which resulted in significant reductions in the frequency of attacks.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We identified and functionally characterized a novel\n                      <jats:italic>SERPING1<\/jats:italic>\n                      splice-site variant, c.1029\u2009+\u20092T\u2009&gt;\u2009A, which disrupts canonical mRNA splicing, primarily through exon 6 skipping, leading to C1-INH haploinsufficiency and type I HAE. Our retrospective analysis expands the mutational spectrum of\n                      <jats:italic>SERPING1<\/jats:italic>\n                      and demonstrates the clinical efficacy of Lanadelumab as a long-term prophylactic therapy. These findings underscore the importance of integrating genetic testing and functional validation in the diagnosis and management of HAE.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04421-3","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T15:17:55Z","timestamp":1780413475000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel SERPING1 splice-site variant (c.1029\u2009+\u20092T\u2009&gt;\u2009A) causing hereditary angioedema type I: functional characterization and clinical analysis"],"prefix":"10.1186","volume":"21","author":[{"given":"Weili","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjin","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianghua","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenchao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuxing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoji","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixiu","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenglong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"4421_CR1","doi-asserted-by":"publisher","first-page":"1554940","DOI":"10.3389\/falgy.2025.1554940","volume":"6","author":"W Du","year":"2025","unstructured":"Du W, Yang K, Zhang Q, Lin X, Zhang W, Guo W, Meng Z, Wang S. 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