De Novo or inherited : gonosomal mosaicism in hereditary angioedema due to C1 inhibitor deficiency
Batlle-Masó, Laura (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Perurena-Prieto, Janire (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Viñas-Giménez, Laura (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Aguiló-Cucurull, Aina (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Fernández-Álvarez, Paula (Hospital Universitari Vall d'Hebron)
Gil-Serrano, Johana (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Guilarte, Mar (Universitat Autònoma de Barcelona. Departament de Medicina)
Colobrán Oriol, Roger (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)

Data:	2025
Resum:	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.
Ajuts:	Instituto de Salud Carlos III PI20/00761 Instituto de Salud Carlos III PI23/00161
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Hereditary angioedema ; C1 inhibitor deficiency ; SERPING1 ; Somatic variant ; Gonosomal mosaicism ; Genetic counseling
Publicat a:	Frontiers in immunology, Vol. 16 (February 2025) , ISSN 1664-3224

DOI: 10.3389/fimmu.2025.1550380
PMID: 39981253

9 p, 4.1 MB

El registre apareix a les col·leccions:
Articles > Articles de recerca
Articles > Articles publicats