Hereditary Angioedema: Clinical and Genetic Research. Summary of the Doctoral Thesis

Abstract

Hereditary angioedema (HAE) is a rare, potentially life-threatening, autosomal dominant disorder, the diagnosis and management of which continue to pose significant challenges in both clinical practice and research. Despite increasing availability of molecular diagnostic tools and targeted therapies, HAE is often diagnosed with delay or misclassified as other types of angioedema. Due to the wide spectrum of clinical manifestations, underlying genetic heterogeneity, and the need for a personalized management approach, research into HAE remains of high relevance both in Latvia and internationally. The dissertation “Hereditary angioedema: clinical and genetic research” is dedicated to the comprehensive characterization of this disease within the Latvian patient population. The pathogenesis of HAE primarily results from a quantitative and/or functional deficiency of C1 esterase inhibitor (C1-INH), caused by pathogenic variants in genes such as SERPING1, F12, PLG, ANGPT1, KNG1, MYOF, or HS3ST6. Clinically, it presents with recurrent angioedema of the skin, gastrointestinal tract, and airways. The primary aims of the study were to characterize the clinical features of HAE, identify disease-causing genetic variants, and explore potential biomarkers for improved diagnostics. The study included all diagnosed HAE patients in Latvia, as well as individuals with idiopathic angioedema and healthy controls. A comprehensive clinical and epidemiological evaluation was performed, based on data extracted from medical records, structured interviews, and patient-reported questionnaires. Standard genetic analysis was performed using Sanger sequencing of the SERPING1 gene in patients with HAE type I/II and of the F12, PLG, ANGPT1 gene regions in patients with suspected HAE with normal C1 inhibitor levels and function (nC1-INH HAE). Advanced genetic analysis was conducted using genome sequencing (GS) to identify rare non-coding and structural variants in HAE type I/II patients in whom no pathogenic variant was detected by standard genetic testing, and using exome sequencing (ES) for gene panel analysis in patients with suspected nC1-INH HAE. In both patient and control groups, metabolomic profiling of blood samples was performed using liquid chromatography-mass spectrometry (LC-MS) to identify novel biomarkers for HAE diagnosis. The study revealed that the prevalence of HAE in Latvia is lower than reported in the literature and in other countries. The clinical presentation of Latvian patients, including edema localization, prodromal symptoms, and trigger factors, was largely consistent with previously published data. However, a significant diagnostic delay from symptom onset to confirmation was observed, highlighting underrecognition of the disease in clinical settings. Standard genetic testing using Sanger sequencing identified causative SERPING1 variants in HAE types I and II patients, whereas in the nC1-INH HAE cohort genetic confirmation was achieved in one individual through detection of a pathogenic PLG variant. Advanced genetic analysis, comprising GS and ES, yielded no additional pathogenic findings. GS was unable to detect any rare noncoding or structural variants. These negative findings nonetheless prompted a systematic reevaluation of clinical diagnoses, thereby uncovering alternative causes of clinical symptoms. Furthermore, beyond its capacity to identify novel genetic aberrations and to guide timely, precision-based therapies, GS – as demonstrated by our study – serves an essential role in elucidating the pathogenesis of angioedema and refining diagnostic determinations when extensive genetic screening fails to reveal pathogenic variants. Metabolomic analysis led to the identification of several potential biomarkers for HAE, including isovalerylcarnitine, hydroxyproline and cystine, which may serve as novel indicators for disease detection. Moreover, combinations of multiple metabolites – such as the ratio of hydroxyproline and cystine to creatinine and isovalerylcarnitine (OH-Pro × Cys)/(Cr × IVC) – may constitute an ancillary diagnostic biomarker for HAE. In conclusion, this dissertation offers a comprehensive overview of the clinical variability of HAE in Latvia, contributes to the understanding of its genetic basis, and highlights the diagnostic value of extended genetic and metabolomic investigations. It supports the advancement of early, accurate diagnosis and the development of personalized therapeutic strategies, while also offering practical recommendations for future research directions and improved patient care in hereditary angioedema.