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

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.

Fig. 1

Distribution of causal variants in SERPING1 gene according to the variant type. Frameshift and missense variants were the most common in index cases, followed by gross deletions. All frameshift variants led to incorporation of termination codon. We didn't find any typical nonsense variants

Fig. 2

Distribution of causal variants of SERPING1 gene according to affected exons. Exon 8 was affected in one-third of all cases. Exons 3 and 7 were the second most affected, followed by exon 6 and intronic variants

Fig. 3

Localization of variants identified in Slovakian HAE patients on SERPING1 gene. The upper part of the figure shows exons (colourful boxes) and introns (white boxes) of the SERPING1 gene with marked variants identified in our cohort; the lower part represents equivalent domains of the C1 inhibitor protein; UTR – untranslated region

Fig. 4

Pedigrees of large HAE families with specific causal variant in SERPING1 gene HAE-affected family members carrying the causal variant are shown in black and healthy individuals are depicted by a blank symbol. Deceased family members are shown with a sloping line through the symbol. Divorce is shown as horizontal line connecting 2 symbols with 2 diagonal hash marks. Individuals with only clinical symptoms indicating HAE who were not genetically tested are marked by asterisk (∗). Variant c.1220del was found in 2 large families which are divided and marked as 1) and 2).