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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

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

  • Anita R. Denisova1
  • Natalia G. Kolosova1
  • Natalia A. Geppe1
  • Veronika D. Denisova2,3
  • Vera A. Podzolkova1
  • Irina V. Ozerskaia1
  • Svetlana I. Shatalina1,3
  • Marina D. Shakhnazarova1
  • Yulia V. Ostankova4
  • Nadezhda A. Pechnikova4,5,6
6 affiliations
  1. 1Department of Children’s Diseases, N.F. Filatov Clinical Institute of Children’s Health, Sechenov First Moscow State Medical University, Moscow 119435, Russia
  2. 2Department of Propaedeutics of Children’s Diseases, N.F. Filatov Clinical Institute of Children’s Health, Sechenov First Moscow State Medical University, Moscow 119435, Russia
  3. 3Research Clinical Institute of Childhood of the Ministry of Health of the Moscow Region, Moscow 141009, Russia
  4. 4Saint Petersburg Pasteur Institute, 14 Mira St., Saint Petersburg 197101, Russia
  5. 5Elpida BioPharm P.C., 54636 Thessaloniki, Greece
  6. 6Laboratory of Chemical Engineering A’, Department of Chemical Engineering, Faculty of Engineering, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
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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.

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Cite

BibTeXRIS
BibTeX
@article{denisova2026hereditary,
  title = {{Hereditary Angioedema with Normal C1-Inhibitor in Children: Diagnostic Challenges, Novel Mutations in MYOF, F12, and HS3ST6, and the Role of Bioinformatics Analysis}},
  author = {Anita R. Denisova and Natalia G. Kolosova and Natalia A. Geppe and Veronika D. Denisova and Vera A. Podzolkova and Irina V. Ozerskaia and Svetlana I. Shatalina and Marina D. Shakhnazarova and Yulia V. Ostankova and Nadezhda A. Pechnikova},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27219551},
  url = {https://www.mdpi.com/1422-0067/27/21/9551},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Hereditary Angioedema with Normal C1-Inhibitor in Children: Diagnostic Challenges, Novel Mutations in MYOF, F12, and HS3ST6, and the Role of Bioinformatics Analysis
AU  - Anita R. Denisova
AU  - Natalia G. Kolosova
AU  - Natalia A. Geppe
AU  - Veronika D. Denisova
AU  - Vera A. Podzolkova
AU  - Irina V. Ozerskaia
AU  - Svetlana I. Shatalina
AU  - Marina D. Shakhnazarova
AU  - Yulia V. Ostankova
AU  - Nadezhda A. Pechnikova
PY  - 2026
DA  - 2026/10/26
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219551
UR  - https://www.mdpi.com/1422-0067/27/21/9551
AB  - 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.
SN  - 1422-0067
ER  -