Work

Hereditary Angioedema with Normal C1-Inhibitor in Children: Diagnostic Challenges, Novel Mutations in MYOF, F12, and HS3ST6, and the Role of Bioinformatics Analysis

Year: 2026

Type: article

Abstract: Hereditary angioedema with normal C1 inhibitor (HAE-nC1INH) lacks validated biochemical biomarkers, complicating diagnosis and interpretation of rare genetic variants, particularly in children. To improve molecular characterization of pediatric HAE-nC1INH, we studied 23 children with recurrent non-histaminergic angioedema, normal C4 and C1 inhibitor levels, and no pathogenic SERPING1 variants. All 23 patients underwent whole-exome sequencing, followed by integrated in silico assessment of candidate variants. A rare heterozygous MYOF p.Arg1590Gln variant was identified in one patient and classified as a VUS, with computational analyses suggesting potential functional relevance. Homozygous F12 p.Ala207Pro was identified in two unrelated patients; however, its high population frequency and benign ClinVar classification do not support a causative role. Four HS3ST6 missense variants were detected in five patients; p.Pro199Leu showed the strongest computational evidence of potential functional relevance, whereas the clinical significance of the remaining variants remains uncertain. These findings expand the molecular spectrum of pediatric HAE-nC1INH and support combining sequencing with prioritization of variants in relevant genes. Functional studies are required to confirm causality before clinical implementation.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27219551