Complex analysis of the national Hereditary angioedema cohort in Slovakia - Identification of 12 novel variants in SERPING1 gene

Adam Markocsy; Katarina Hrubiskova; Martin Hrubisko; Tomas Freiberger; Hana Grombirikova; Lenka Dolesova; Ludmila Slivka Vavrova; Regina Lohajova Behulova; Martina Ondrusova; Peter Banovcin; Karolina Vorcakova; Milos Jesenak

doi:10.1016/j.waojou.2024.100885

Complex analysis of the national Hereditary angioedema cohort in Slovakia - Identification of 12 novel variants in SERPING1 gene

World Allergy Organ J. 2024 Mar 7;17(3):100885. doi: 10.1016/j.waojou.2024.100885. eCollection 2024 Mar.

Authors

Affiliations

¹ National Centre for Hereditary Angioedema, Clinic of Children and Adolescents, Clinics of Pulmonology and Phthisiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, University Hospital in Martin, Slovakia.
² Centre for Hereditary Angioedema, 5th Clinic of Internal Medicine, Faculty of Medicine, Comenius University in Bratislava, University Hospital Bratislava, Bratislava, Slovakia.
³ Department of Clinical Immunology and Allergology, St. Elisabeth Cancer Institute in Bratislava, Slovakia.
⁴ Centre for Cardiovascular Surgery and Transplantation, Brno, Czech Republic.
⁵ Faculty of Medicine, Masaryk University, Brno, Czech Republic.
⁶ Department of Medical Genetics, St. Elisabeth Cancer Institute in Bratislava, Slovakia.
⁷ Pharm-In, Ltd., Bratislava, Slovakia.
⁸ Faculty of Public Health, Slovak Medical University, Bratislava, Slovakia.
⁹ Clinic of Dermatovenerology, Jessenius Faculty of Medicine, Comenius University in Bratislava, University Hospital in Martin, Slovakia.
¹⁰ Department of Clinical Immunology and Allergology, Jessenius Faculty of Medicine, Comenius University in Bratislava, University Hospital in Martin, Slovakia.

Abstract

Background: Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterised by acute episodes of non-pruritic skin and submucosal swelling caused by increase in vascular permeability.

Objective: Here we present the first complex analysis of the National HAE Slovakian cohort with the detection of 12 previously un-published genetic variants in SERPING1 gene.

Methods: In patients diagnosed with hereditary angioedema caused by deficiency or dysfunction of C1 inhibitor (C1-INH-HAE) based on clinical manifestation and complement measurements, SERPING1 gene was tested by DNA sequencing (Sanger sequencing/massive parallel sequencing) and/or multiplex ligation-dependent probe amplification for detection of large rearrangements.

Results: The Slovakian national cohort consisted of 132 living patients with confirmed HAE. We identified 51 index cases (32 families, 19 sporadic patients/112 adults, 20 children). One hundred seventeen patients had HAE caused by deficiency of C1 inhibitor (C1-INH-HAE-1) and 15 patients had HAE caused by dysfunction of C1 inhibitor (C1-INH-HAE-2). The prevalence of HAE in Slovakia has recently been calculated to 1:41 280 which is higher than average calculated prevalence. The estimated incidence was 1:1360 000. Molecular-genetic testing of the SERPING1 gene found 22 unique causal variants in 26 index cases, including 12 previously undescribed and unreported.

Conclusion: The first complex report about epidemiology and genetics of the Slovakian national HAE cohort expands the knowledge of the C1-INH-HAE genetics. Twelve novel causal variants were present in the half of the index cases. A higher percentage of inframe variants comparing to other studies was observed. Heterozygous deletion of exon 3 found in a large C1-INH-HAE-1 family probably causes the dysregulation of the splicing isoforms balance and leads to the decrease of full-length C1-INH level.

Keywords: Angioedemas; Complement C1 inhibitor protein; Genetic testing; Hereditary/epidemiology; Hereditary/genetics; Slovakia.