A hereditary angioedema screening in two villages, based on an index case, and identification of a novel mutation, "1033G>T", at the SERPING1 gene

Abstract

Introduction: Hereditary angioedema (HAE) may be fatal and diagnosis can be delayed up to 10 years. We aimed to screen HAE in two villages based on an index case of HAE and to investigate for the mutation of the C1 esterase inhibitor (C1-INH) gene.

Material and methods: A total of 124 people were screened in two villages. The frequency and severity of symptoms were scored. C4, C1-INH levels and C1-INH activity were measured. We investigated for mutations of the C1-INH gene.

Results: Thirty-five cases of type I HAE and 7 cases of type II HAE were determined. Thirty-one (73.8%) patients diagnosed with HAE were 18 years old or younger. There was a positive correlation between C4 levels, C1-INH levels (p < 0.0001, r = 0.81), and C1-INH activity levels (p < 0.0001, r = 0.631) and between the age at diagnosis and severity score (p < 0.0001, r = 0.651). A positive correlation was found between the age at first symptom onset and C4 levels (p = 0.002, r = 0.774), and C1-INH levels (p = 0.006, r = 0.714). A marginally significant negative correlation was found between C1-INH activity levels and severity scores (p = 0.1, r = -0.515). We identified a novel heterozygous 1033G>T missense variant of the C1-INH gene, SERPING1, in patients with type I HAE.

Conclusions: There are long delay periods in the diagnosis of HAE and when the index case is present, family screening may be very important and even life-saving, in particular, in paediatric patients without symptoms. Furthermore, the present study provides evidence to link a novel mutation, c.1033G>T, to the development of HAE in a large HAE family from Turkey.

Keywords: 1033G>T; SERPING1; hereditary angioedema.

Figure 1

A – Correlation between C4 levels and C1 esterase inhibitor levels of cases. B – Correlation between C4 levels and C1 esterase inhibitor activity levels

Figure 2

Relationship between HAE severity scores and C1 esterase inhibitor activity levels

Figure 3

A – The HAE family pedigree. Note that the black boxes indicate type I HAE; however, subjects II.17, III.23, III.24, III.25, IV.38, IV.39 and IV.40 have type II HAE, interestingly, in the same family. B – Display of the Integrative Genomics Viewer (IGV) showing the SERPING1 novel heterozygous c.1033G>T missense variant. The grey letter represents the wildtype nucleotides and the red letter represents a single base-nucleotide alteration. C – The SERPING1 gene structure and the location of the functional domain (serpin protease inhibitor) are indicated. The conservation of 345^th glycine residue among species. Conserved glycine is shown with the arrow (Information Conservation). D – The wild-type protein and defective protein, respectively, covering the regions of serpin protease inhibitor, as presented in the SWISS-MODEL work space window