Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association

Abstract

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA) are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T). Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444) or group 2 (missense, excluding mutations at Arg444). Significant differences were found in the clinical severity score (P = 0.005), prevalence of laryngeal (P = 0.040) and facial (P = 0.013) oedema, and long-term prophylaxis (P = 0.023) between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038). Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a clear effect on C1-INH function might be responsible for a more severe disease phenotype.

Mutational spectrum of the SERPING1 gene in Swiss patients with hereditary angioedema

“…In eight of the nine families investigated with a diagnosis of HAE, mutations in the SERPING1 gene were identified. The diversity of the identified mutations confirms the heterogeneity of mutations observed in other European countries . Missense mutations and nucleotide duplications with consecutive frameshift constitute the largest groups of mutations, which is in line with studies of other populations .…”

The functional promoter F12‐46C/T variant predicts the asymptomatic phenotype of C1‐INH‐HAE

“…Despite great efforts in clarifying the severity of the disease, variability in clinical expression remains an unsolved issue. Mutation type, specifically mutations with a clear effect on C1‐INH function, accounts for a more severe disease phenotype, the need for long‐term prophylaxis, and earlier disease onset . However, only a small proportion of the variance can be predicted with the SERPING1 gene mutation type, and even in families with several affected members sharing the same mutation, differences in disease severity are well known, and by some estimations, up to 14% of carriers of the SERPING1 gene mutation remain asymptomatic throughout their entire life .…”

Deletions in <b><i>SERPING1</i></b> Lead to Lower C1 Inhibitor Function: Lower C1 Inhibitor Function Can Predict Disease Severity

“…A clear correlation between SERPING1 mutations and disease phenotype was not affirmed by previous reports [7, 23]. Recent studies reported that C1-INH-HAE was started later in those with missense mutations and they experienced a significantly low frequency of attacks [4, 9, 11]. All these studies have mainly focused on missense mutations, and the groups were divided as “missense” and “other type of SERPING1 defects.” Unlike these studies, we defined every mutation type as a different group and tried to examine the effects of each mutation type on the clinical phenotype.…”

“…Several studies have been conducted to clarify a possible association between mutation types, and clinical phenotypes. Some data showed no close association between mutation type and the phenotypic expression of C1-INH-HAE [7, 8], but others reported that missense mutations had favorable outcomes on C1 inhibitor antigenic levels, clinical severity score, and age at onset of symptoms, respectively [4, 9-11]. Although the genetic background of the disease has already been determined from various populations, there are limited data about genetic properties of C1-INH-HAE from Turkish patients [12].…”