Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort
Hana Grombirikova,
Viktor Bily,
Premysl Soucek
et al.
Abstract:Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare and life-threatening condition characterized by recurrent localized edema. We conducted a systematic screening of SERPING1 defects in a cohort of 207 Czech patients from 85 families with C1-INH-HAE. Our workflow involved a combined strategy of sequencing extended to UTR and deep intronic regions, advanced in silico prediction tools, and mRNA-based functional assays. This approach allowed us to detect a causal variant in all families ex… Show more
“…The prevalence of C1–INH-HAE in the Slovak Republic according to this study is currently 1:41 280 and the incidence 1:1 360 000 (total population: 5 449 270 according to the 2021 population census). The prevalence is higher in comparison to data from other European countries: Sweden – 1:66 000, 50 Italy – 1:65 000, 51 Denmark – 1:70 900, 20 Greece −1:90 000, 52 Spain – 1:91 700, 53 the Czech Republic – 1:52 307, 6 and higher than average calculated prevalence 1:50 000. 2 …”
Section: Discussionmentioning
confidence: 57%
“…Variation type distribution in our cohort is different compared to neighbouring countries. 6 , 7 We found a higher proportion of frameshift and inframe variants. Proportion of missense variants and gross deletions is similar to distribution according to the LOVD database.…”
Section: Discussionmentioning
confidence: 58%
“…Our cohort has higher percentage of inframe variants (11,5%) comparing to other studies. 5 , 6 , 7 Interpretation is challenging due to limitations of in-silico prediction tools and evaluation of impact on protein structure. All our novel inframe variants are rated as likely pathogenic according to ACMG criteria considering family history and segregation analysis.…”
Section: Discussionmentioning
confidence: 99%
“…Causative or probably causative variants were detected in 206 out of 207 (56 unique pathogenic or likely pathogenic sequence variants were found). 6 In the study of Hungarian HAE patients (neighbouring country of Slovakia), missense variants were found in 30.1%, large deletions or duplications in 20.6%, frameshift variants in 19.1%, nonsense variants in 17.6%, and splicing variants in 11.8% of the index cases. 7 …”
“…The prevalence of C1–INH-HAE in the Slovak Republic according to this study is currently 1:41 280 and the incidence 1:1 360 000 (total population: 5 449 270 according to the 2021 population census). The prevalence is higher in comparison to data from other European countries: Sweden – 1:66 000, 50 Italy – 1:65 000, 51 Denmark – 1:70 900, 20 Greece −1:90 000, 52 Spain – 1:91 700, 53 the Czech Republic – 1:52 307, 6 and higher than average calculated prevalence 1:50 000. 2 …”
Section: Discussionmentioning
confidence: 57%
“…Variation type distribution in our cohort is different compared to neighbouring countries. 6 , 7 We found a higher proportion of frameshift and inframe variants. Proportion of missense variants and gross deletions is similar to distribution according to the LOVD database.…”
Section: Discussionmentioning
confidence: 58%
“…Our cohort has higher percentage of inframe variants (11,5%) comparing to other studies. 5 , 6 , 7 Interpretation is challenging due to limitations of in-silico prediction tools and evaluation of impact on protein structure. All our novel inframe variants are rated as likely pathogenic according to ACMG criteria considering family history and segregation analysis.…”
Section: Discussionmentioning
confidence: 99%
“…Causative or probably causative variants were detected in 206 out of 207 (56 unique pathogenic or likely pathogenic sequence variants were found). 6 In the study of Hungarian HAE patients (neighbouring country of Slovakia), missense variants were found in 30.1%, large deletions or duplications in 20.6%, frameshift variants in 19.1%, nonsense variants in 17.6%, and splicing variants in 11.8% of the index cases. 7 …”
“…The SERPING1 gene is composed of eight exons and seven introns. Normally, this gene undergoes alternative splicing; however, the physiological role of alternative transcripts is unclear to this day [11,12]. All types of pathogenic variants are described for the gene: missense-32.2%, minor deletions and insertions-36.2%, deletions and duplications-8.3%, splicing affected variants-10.6%, nonsense-9.1% and promoter-3.7%?…”
Variants that affect splice sites comprise 14.3% of all pathogenic variants in the SERPING1 gene; more than half of them are located outside the canonical sites. To make a clinical decision concerning patients with such variants, it is essential to know the exact way in which the effect of the variant would be realized. The optimal approach to determine the consequences is considered to be mRNA analysis. In the current study, we present the results of functional analysis of two previously non-described variants in the SERPING1 gene (NM_000062.3) affecting intron 4: c.686-1G>A and c.685+4dup, which were detected in members of two Russian families with autosomal dominant inheritance of angioedema type 1. Analysis of the patients’ mRNA (extracted from whole blood) showed that the SERPING1(NM_000062.3):c.685+4dup variant leads to the loss of the donor splice site and the activation of the cryptic site in exon 4: r.710_745del (p.Gly217_Pro228del), while the SERPING1(NM_000062.3):c.686-1G>A variant leads to the skipping of exon 5: r.746_949del (p.Asp229_Ser296del).
Background : When the diagnosis of HAE is known in a family and a child is born, the question of early diagnosis at birth arises. Indeed, the first attacks may appear as early as birth. The importance of early diagnosis comes up against biological issues: C1 Inhibitor (C1 INH) and C4 levels can be low at birth, generally in the range of 60 to 100% of adult reference values, due to the immaturity of the complement system. As most of complement proteins, their levels normalize after one year of life. We report the opposite case, in two newborns.
Case presentation: A women with well documented hereditary angioedema type II C1Inh deficiency gave birth to 2 children 4 years apart. The 2 children had a functional C1Inh assay at 8 and 7 months of age respectively: the results showed a normal functional C1Inh level. A genetic investigation was nevertheless carried out, which revealed the presence of the mother’s mutation in both children. Monitoring of C1Inh function at 3 and 4 years of age finally showed a pathological reduction in C1Inh function.
Conclusion : These cases lead us to recommend, for the early detection of children, genetic research of the mutation of the index parent in the child rather than the C1Inh assay
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.