De Novo or inherited: gonosomal mosaicism in hereditary angioedema due to C1 inhibitor deficiency
Hereditary angioedema (HAE) is a rare genetic disease, characterized by transient and self-limiting episodes of subcutaneous or submucosal swelling that spontaneously resolve within two to five days. The most common form of HAE, HAE-C1-INH, is caused by deleterious mutations in the SERPING1 gene, en...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1550380/full |
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| author | Laura Batlle-Masó Laura Batlle-Masó Laura Batlle-Masó Janire Perurena-Prieto Janire Perurena-Prieto Janire Perurena-Prieto Laura Viñas-Giménez Laura Viñas-Giménez Laura Viñas-Giménez Aina Aguiló-Cucurull Aina Aguiló-Cucurull Paula Fernández-Álvarez Johana Gil-Serrano Johana Gil-Serrano Johana Gil-Serrano Mar Guilarte Mar Guilarte Mar Guilarte Roger Colobran Roger Colobran Roger Colobran Roger Colobran |
| author_facet | Laura Batlle-Masó Laura Batlle-Masó Laura Batlle-Masó Janire Perurena-Prieto Janire Perurena-Prieto Janire Perurena-Prieto Laura Viñas-Giménez Laura Viñas-Giménez Laura Viñas-Giménez Aina Aguiló-Cucurull Aina Aguiló-Cucurull Paula Fernández-Álvarez Johana Gil-Serrano Johana Gil-Serrano Johana Gil-Serrano Mar Guilarte Mar Guilarte Mar Guilarte Roger Colobran Roger Colobran Roger Colobran Roger Colobran |
| author_sort | Laura Batlle-Masó |
| collection | DOAJ |
| description | Hereditary angioedema (HAE) is a rare genetic disease, characterized by transient and self-limiting episodes of subcutaneous or submucosal swelling that spontaneously resolve within two to five days. The most common form of HAE, HAE-C1-INH, is caused by deleterious mutations in the SERPING1 gene, encoding the C1-Inhibitor protein, and its diagnosis is confirmed by decreased C1-INH function. Distinctively from other genetic forms of HAE, up to 15-20% of HAE-C1-INH cases are sporadic caused by de novo mutations. Here, we report a patient with apparently sporadic HAE-C1-INH. The patient had compatible clinical symptoms and a markedly low C1-INH function, and the parents showed normal values of C4 and normal C1-INH function. In the patient, we identified a novel splice site mutation in SERPING1 (c.890-1G>C) and, by cDNA analysis, we confirmed its pathogenicity. Despite normal C1-INH function in the parents, we found that the mother was, unexpectedly, a mutation carrier. The inverted profile of the Sanger peaks compared with the patient, strongly suggested the presence of gonosomal mosaicism in the mother. We confirmed and quantified the mosaicism in different tissues by high depth NGS-based deep amplicon sequencing, showing a similar frequency of the variant ranging from 17 to 23%. In this study, we present the first case of gonosomal mosaicism in a family with a single child affected with HAE-C1-INH from unaffected parents. Our results underscore the importance of parental genetic testing in all patients, regardless of whether the parents are affected, and highlights the implications of gonosomal mosaicism for genetic counseling. |
| format | Article |
| id | doaj-art-8a6747e58521469fb40b1a7f6f171b0e |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-8a6747e58521469fb40b1a7f6f171b0e2025-02-06T07:09:06ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15503801550380De Novo or inherited: gonosomal mosaicism in hereditary angioedema due to C1 inhibitor deficiencyLaura Batlle-Masó0Laura Batlle-Masó1Laura Batlle-Masó2Janire Perurena-Prieto3Janire Perurena-Prieto4Janire Perurena-Prieto5Laura Viñas-Giménez6Laura Viñas-Giménez7Laura Viñas-Giménez8Aina Aguiló-Cucurull9Aina Aguiló-Cucurull10Paula Fernández-Álvarez11Johana Gil-Serrano12Johana Gil-Serrano13Johana Gil-Serrano14Mar Guilarte15Mar Guilarte16Mar Guilarte17Roger Colobran18Roger Colobran19Roger Colobran20Roger Colobran21Infection and Immunity in Pediatric Patients Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, SpainPediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron (HUVH), Barcelona, Catalonia, SpainPompeu Fabra University (UPF), Barcelona, Catalonia, SpainTranslational Immunology Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, SpainImmunology Division, Vall d’Hebron University Hospital (HUVH), Barcelona, Catalonia, SpainDepartment of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Bellaterra, Catalonia, SpainTranslational Immunology Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, SpainImmunology Division, Vall d’Hebron University Hospital (HUVH), Barcelona, Catalonia, SpainDepartment of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Bellaterra, Catalonia, SpainTranslational Immunology Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, SpainImmunology Division, Vall d’Hebron University Hospital (HUVH), Barcelona, Catalonia, SpainDepartment of Clinical and Molecular Genetics, Vall d’Hebron University Hospital (HUVH), Barcelona, Catalonia, SpainDepartment of Allergy, Vall d’Hebron University Hospital (HUVH), Barcelona, Catalonia, SpainAllergy Research Unit, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain0Department of Medicine, Autonomous University of Barcelona (UAB), Bellaterra, Catalonia, SpainDepartment of Allergy, Vall d’Hebron University Hospital (HUVH), Barcelona, Catalonia, SpainAllergy Research Unit, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain0Department of Medicine, Autonomous University of Barcelona (UAB), Bellaterra, Catalonia, SpainTranslational Immunology Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, SpainImmunology Division, Vall d’Hebron University Hospital (HUVH), Barcelona, Catalonia, SpainDepartment of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Bellaterra, Catalonia, SpainDepartment of Clinical and Molecular Genetics, Vall d’Hebron University Hospital (HUVH), Barcelona, Catalonia, SpainHereditary angioedema (HAE) is a rare genetic disease, characterized by transient and self-limiting episodes of subcutaneous or submucosal swelling that spontaneously resolve within two to five days. The most common form of HAE, HAE-C1-INH, is caused by deleterious mutations in the SERPING1 gene, encoding the C1-Inhibitor protein, and its diagnosis is confirmed by decreased C1-INH function. Distinctively from other genetic forms of HAE, up to 15-20% of HAE-C1-INH cases are sporadic caused by de novo mutations. Here, we report a patient with apparently sporadic HAE-C1-INH. The patient had compatible clinical symptoms and a markedly low C1-INH function, and the parents showed normal values of C4 and normal C1-INH function. In the patient, we identified a novel splice site mutation in SERPING1 (c.890-1G>C) and, by cDNA analysis, we confirmed its pathogenicity. Despite normal C1-INH function in the parents, we found that the mother was, unexpectedly, a mutation carrier. The inverted profile of the Sanger peaks compared with the patient, strongly suggested the presence of gonosomal mosaicism in the mother. We confirmed and quantified the mosaicism in different tissues by high depth NGS-based deep amplicon sequencing, showing a similar frequency of the variant ranging from 17 to 23%. In this study, we present the first case of gonosomal mosaicism in a family with a single child affected with HAE-C1-INH from unaffected parents. Our results underscore the importance of parental genetic testing in all patients, regardless of whether the parents are affected, and highlights the implications of gonosomal mosaicism for genetic counseling.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1550380/fullhereditary angioedemaC1 inhibitor deficiencySERPING1somatic variantgonosomal mosaicismgenetic counseling |
| spellingShingle | Laura Batlle-Masó Laura Batlle-Masó Laura Batlle-Masó Janire Perurena-Prieto Janire Perurena-Prieto Janire Perurena-Prieto Laura Viñas-Giménez Laura Viñas-Giménez Laura Viñas-Giménez Aina Aguiló-Cucurull Aina Aguiló-Cucurull Paula Fernández-Álvarez Johana Gil-Serrano Johana Gil-Serrano Johana Gil-Serrano Mar Guilarte Mar Guilarte Mar Guilarte Roger Colobran Roger Colobran Roger Colobran Roger Colobran De Novo or inherited: gonosomal mosaicism in hereditary angioedema due to C1 inhibitor deficiency Frontiers in Immunology hereditary angioedema C1 inhibitor deficiency SERPING1 somatic variant gonosomal mosaicism genetic counseling |
| title | De Novo or inherited: gonosomal mosaicism in hereditary angioedema due to C1 inhibitor deficiency |
| title_full | De Novo or inherited: gonosomal mosaicism in hereditary angioedema due to C1 inhibitor deficiency |
| title_fullStr | De Novo or inherited: gonosomal mosaicism in hereditary angioedema due to C1 inhibitor deficiency |
| title_full_unstemmed | De Novo or inherited: gonosomal mosaicism in hereditary angioedema due to C1 inhibitor deficiency |
| title_short | De Novo or inherited: gonosomal mosaicism in hereditary angioedema due to C1 inhibitor deficiency |
| title_sort | de novo or inherited gonosomal mosaicism in hereditary angioedema due to c1 inhibitor deficiency |
| topic | hereditary angioedema C1 inhibitor deficiency SERPING1 somatic variant gonosomal mosaicism genetic counseling |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1550380/full |
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