The use of comprehensive screening approaches and functional analyses has proven beneficial in improving the diagnosis and management of hereditary angioedema (HAE) due to C1 inhibitor deficiency (C1-INH-HAE), according to findings from a retrospective study conducted in the Czech Republic.
C1-INH-HAE is recognized as a rare, life-threatening condition in which patients experience recurrent episodes of localized edema. Based on immunologic features, HAE can be classified into 3 types:
- HAE type 1 (HAE-1): patients experience a deficiency in both antigenic and functional C1 inhibitor (C1) levels
- HAE type 2 (HAE-2): patients exhibit a normal C1-INH protein concentration but impaired C1-INH function
- HAE with normal C1-inhibitor (nC1-INH-HAE): patients experience mutations predominantly in the factor XII (F12) and plasminogen (PLG) genes
HAE-1 and HAE-2, both of which are inherited in an autosomal dominant mode, are caused by pathogenic variants in SERPING1—the gene encoding C1-INH that is located in the 11q12-q13.1 chromosome. Although SERPING1 is a naturally alternatively spliced gene, the role played by alternative transcripts remains to be elucidated. In fact, SERPING1 comprises 8 exons and 7 introns.
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The researchers sought to perform a systematic screening of SERPING1 defects in a cohort of 207 Czech patients from 85 unrelated Czech families with C1-INH-HAE. The presence of C1-INH-HAE was determined based on clinical signs and after measurement of serum C1-inhibitor concentration, C1-inhibitor activity, and C4 levels.
The assessment conducted by the Czech National HAE Cohort involved a combination approach that used sequencing extended to untranslated regions and deep intronic regions, advanced in silico prediction tools, and mRNA-based functional assays.
Use of this strategy permitted the detection of a causal variant in all but one of the families and the identification of 56 different variants, which included 5 novel variants that are likely to be causal in nature.
In addition, the investigators conducted an exploration of the functional impact of 2 splicing variants—that is, c.550+3A>C and c.686-7C>G—with the use of real-time polymerase chain reaction mRNA analysis and minigene assays. Of note, a higher percentage of detected splicing variants was observed in the study cohort compared with other central European populations and the worldwide Leiden Open Variation Database.
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A significant association was demonstrated between HAE-1 missense variants and delayed disease onset compared with the null variants (P =.023). Further, a significant correlation was observed between presence of the SERPING1 variant c.-21 T>C in the trans position to causal variants and the following variables:
- Frequency of HAE attacks per year (P =.018)
- Lower age at disease onset (P =.024)
- Higher Clinical Severity Score (P =.048)
“Overall, our study provides new insights into the genetic landscape of C1-INH-HAE in the Czech population, including the identification of novel variants and a better understanding of genotype-phenotype correlations,” the authors explained. “Using targeted panel sequencing, which is becoming standard, we can analyze all the SERPING1 regions, as well as other genes associated with HAE in one step,” they noted. “Several variants possibly affecting SERPING1 expression and splicing still await functional evidence,” they concluded.
Grombirikova H, Bily V, Soucek P, et al. Systematic approach revealed SERPING1 splicing-affecting variants to be highly represented in the Czech National HAE Cohort. J Clin Immunol. Published online August 25, 2023. doi:10.1007/s10875-023-01565-w