Hereditary angioedema due to C1-inhibitor deficiency in Macedonia: clinical characteristics, novel SERPING1 mutations and genetic factors modifying the clinical phenotype

Abstract

Genetic analysis helped identify the molecular basis of C1-INH-HAE given that causative mutations in SERPING1 were detected in all patients, including an infant before the appearance of clinical symptoms. We identified two novel mutations and further corroborated the genotype-phenotype relationship, wherein mutations with a clear effect on C1-INH function predispose patients to a more severe disease phenotype and CC F12-46C/T predisposes patients to earlier disease onset. KEY MESSAGES • In the present nationwide study, we aimed to characterize on a clinical and molecular basis patients with hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) in the Republic of Macedonia. • Causative mutations in SERPING1 were detected in all 15 C1-INH-HAE patients from six Macedonian families, including an infant, before the appearance of clinical symptoms. • We identified three known mutations and two novel mutations (c.813_818delCAACAA and c.1488T > G). These findings further corroborated the genotype-phenotype relationship, wherein mutations with a clear effect on C1-INH function predispose patients to a more severe disease phenotype and the CC F12-46C/T polymorphism predisposes patients to earlier disease onset.

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

“…Therefore, research on genetic predisposition influencing the clinical expression of the disease and identifying patients who are more likely to develop severe and frequent attacks in comparison to individuals who are more likely to be asymptomatic despite carrying the same disease‐causing SERPING1 gene mutation has been focused on other genes mainly involved in bradykinin metabolism. The most promising functional variant in the F12 gene ( F12 ‐46C/T, rs1801020) was found (also by our group) to be strongly associated with disease onset . Since the association of this F12 variant with disease onset was clearly demonstrated, we speculated that it might also predict 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 .…”

“…In the present study, we investigated whether the frequency of the F12 ‐46C/T variant differs between symptomatic and asymptomatic C1‐INH‐HAE patients and whether it is a modifying genetic factor predisposing to the appearance of symptoms. To achieve that, a large cohort of 88 clinically well‐characterized C1‐INH‐HAE southeastern European patients, including nine, asymptomatic adults, from 42 unrelated families, were analysed for the F12 ‐46C/T variant as described previously . For more details, see Data .…”

“…3,5,6 Therefore, research on genetic predisposition influencing the clinical expression of the disease and identifying patients who are more likely to develop severe and frequent attacks in comparison to individuals who are more likely to be asymptomatic despite carrying the same disease-causing SERPING1 gene mutation has been focused on other genes mainly involved in bradykinin metabolism.The most promising functional variant in the F12 gene (F12-46C/T, rs1801020) was found (also by our group) to be strongly associated with disease onset. 6,7,9 Since the association of this F12 variant with disease onset was clearly demonstrated, we speculated that it might also predict the asymptomatic phenotype of C1-INH-HAE.In the present study, we investigated whether the frequency of the F12-46C/T variant differs between symptomatic and asymptomatic C1-INH-HAE patients and whether it is a modifying genetic factor predisposing to the appearance of symptoms. To achieve that, a large cohort of 88 clinically well-characterized C1-INH-HAE southeastern European patients, including nine, asymptomatic adults, from 42 unrelated families, were analysed for the F12-46C/T variant as described previously.…”

“…The most promising functional variant in the F12 gene (F12-46C/T, rs1801020) was found (also by our group) to be strongly associated with disease onset. 6,7,9 Since the association of this F12 variant with disease onset was clearly demonstrated, we speculated that it might also predict the asymptomatic phenotype of C1-INH-HAE.…”