A novel deep intronic SERPING1 variant as a cause of hereditary angioedema due to C1-inhibitor deficiency

Sofia Vatsiou, Maria Zamanakou, Gedeon Loules, Fotis Psarros, Faidra Parsopoulou, Dorottya Csuka, Anna Valerieva, Maria Staevska, Grzegorz Porebski, Krystyna Obtulowicz, Markus Magerl, Marcus Maurer, Matthaios Speletas, Henriette Farkas, Anastasios E. Germenis

Research output: Contribution to journalArticle

Abstract

Background: In about 5% of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) no mutation in the SERPING1 gene is detected. Methods: C1-INH-HAE cases with no mutation in the coding region of SERPING1 after conventional genotyping were examined for defects in the intronic or untranslated regions of the gene. Using a next-generation sequencing (NGS) platform targeting the entire SERPING1, 14 unrelated C1-INH-HAE patients with no detectable mutations in the coding region of the gene were sequenced. Detected variants with a global minor allele frequency lower than the frequency of C1-INH-HAE (0.002%), were submitted to in silico analysis using ten different bioinformatics tools. Pedigree analysis and examination of their pathogenic effect on the RNA level were performed for filtered in variants. Results: In two unrelated patients, the novel mutation c.-22-155G > T was detected in intron 1 of the SERPING1 gene by the use NGS and confirmed by Sanger sequencing. All bioinformatics tools predicted that the variant causes a deleterious effect on the gene and pedigree analysis showed its co-segregation with the disease. Degradation of the mutated allele was demonstrated by the loss of heterozygosity on the cDNA level. According to the American College of Medical Genetics and Genomics 2015 guidelines the c.-22-155G > T was curated as pathogenic. Conclusions: For the first time, a deep intronic mutation that was detected by NGS in the SERPING1 gene, was proven pathogenic for C1-INH-HAE. Therefore, advanced DNA sequencing methods should be performed in cases of C1-INH-HAE where standard approaches fail to uncover the genetic alteration.

Original languageEnglish
JournalAllergology International
DOIs
Publication statusAccepted/In press - Jan 1 2020

Fingerprint

Hereditary Angioedemas
Mutation
Genes
Pedigree
Computational Biology
Untranslated Regions
Loss of Heterozygosity
Genomics
DNA Sequence Analysis
Gene Frequency
Computer Simulation
Introns
Complementary DNA
Alleles
Guidelines
RNA

Keywords

  • C1-inhibitor deficiency
  • Hereditary angioedema
  • Intronic mutations
  • Next-generation sequencing
  • SERPING1 gene

ASJC Scopus subject areas

  • Immunology and Allergy

Cite this

Vatsiou, S., Zamanakou, M., Loules, G., Psarros, F., Parsopoulou, F., Csuka, D., ... Germenis, A. E. (Accepted/In press). A novel deep intronic SERPING1 variant as a cause of hereditary angioedema due to C1-inhibitor deficiency. Allergology International. https://doi.org/10.1016/j.alit.2019.12.009

A novel deep intronic SERPING1 variant as a cause of hereditary angioedema due to C1-inhibitor deficiency. / Vatsiou, Sofia; Zamanakou, Maria; Loules, Gedeon; Psarros, Fotis; Parsopoulou, Faidra; Csuka, Dorottya; Valerieva, Anna; Staevska, Maria; Porebski, Grzegorz; Obtulowicz, Krystyna; Magerl, Markus; Maurer, Marcus; Speletas, Matthaios; Farkas, Henriette; Germenis, Anastasios E.

In: Allergology International, 01.01.2020.

Research output: Contribution to journalArticle

Vatsiou, S, Zamanakou, M, Loules, G, Psarros, F, Parsopoulou, F, Csuka, D, Valerieva, A, Staevska, M, Porebski, G, Obtulowicz, K, Magerl, M, Maurer, M, Speletas, M, Farkas, H & Germenis, AE 2020, 'A novel deep intronic SERPING1 variant as a cause of hereditary angioedema due to C1-inhibitor deficiency', Allergology International. https://doi.org/10.1016/j.alit.2019.12.009
Vatsiou, Sofia ; Zamanakou, Maria ; Loules, Gedeon ; Psarros, Fotis ; Parsopoulou, Faidra ; Csuka, Dorottya ; Valerieva, Anna ; Staevska, Maria ; Porebski, Grzegorz ; Obtulowicz, Krystyna ; Magerl, Markus ; Maurer, Marcus ; Speletas, Matthaios ; Farkas, Henriette ; Germenis, Anastasios E. / A novel deep intronic SERPING1 variant as a cause of hereditary angioedema due to C1-inhibitor deficiency. In: Allergology International. 2020.
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abstract = "Background: In about 5{\%} of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) no mutation in the SERPING1 gene is detected. Methods: C1-INH-HAE cases with no mutation in the coding region of SERPING1 after conventional genotyping were examined for defects in the intronic or untranslated regions of the gene. Using a next-generation sequencing (NGS) platform targeting the entire SERPING1, 14 unrelated C1-INH-HAE patients with no detectable mutations in the coding region of the gene were sequenced. Detected variants with a global minor allele frequency lower than the frequency of C1-INH-HAE (0.002{\%}), were submitted to in silico analysis using ten different bioinformatics tools. Pedigree analysis and examination of their pathogenic effect on the RNA level were performed for filtered in variants. Results: In two unrelated patients, the novel mutation c.-22-155G > T was detected in intron 1 of the SERPING1 gene by the use NGS and confirmed by Sanger sequencing. All bioinformatics tools predicted that the variant causes a deleterious effect on the gene and pedigree analysis showed its co-segregation with the disease. Degradation of the mutated allele was demonstrated by the loss of heterozygosity on the cDNA level. According to the American College of Medical Genetics and Genomics 2015 guidelines the c.-22-155G > T was curated as pathogenic. Conclusions: For the first time, a deep intronic mutation that was detected by NGS in the SERPING1 gene, was proven pathogenic for C1-INH-HAE. Therefore, advanced DNA sequencing methods should be performed in cases of C1-INH-HAE where standard approaches fail to uncover the genetic alteration.",
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T1 - A novel deep intronic SERPING1 variant as a cause of hereditary angioedema due to C1-inhibitor deficiency

AU - Vatsiou, Sofia

AU - Zamanakou, Maria

AU - Loules, Gedeon

AU - Psarros, Fotis

AU - Parsopoulou, Faidra

AU - Csuka, Dorottya

AU - Valerieva, Anna

AU - Staevska, Maria

AU - Porebski, Grzegorz

AU - Obtulowicz, Krystyna

AU - Magerl, Markus

AU - Maurer, Marcus

AU - Speletas, Matthaios

AU - Farkas, Henriette

AU - Germenis, Anastasios E.

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N2 - Background: In about 5% of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) no mutation in the SERPING1 gene is detected. Methods: C1-INH-HAE cases with no mutation in the coding region of SERPING1 after conventional genotyping were examined for defects in the intronic or untranslated regions of the gene. Using a next-generation sequencing (NGS) platform targeting the entire SERPING1, 14 unrelated C1-INH-HAE patients with no detectable mutations in the coding region of the gene were sequenced. Detected variants with a global minor allele frequency lower than the frequency of C1-INH-HAE (0.002%), were submitted to in silico analysis using ten different bioinformatics tools. Pedigree analysis and examination of their pathogenic effect on the RNA level were performed for filtered in variants. Results: In two unrelated patients, the novel mutation c.-22-155G > T was detected in intron 1 of the SERPING1 gene by the use NGS and confirmed by Sanger sequencing. All bioinformatics tools predicted that the variant causes a deleterious effect on the gene and pedigree analysis showed its co-segregation with the disease. Degradation of the mutated allele was demonstrated by the loss of heterozygosity on the cDNA level. According to the American College of Medical Genetics and Genomics 2015 guidelines the c.-22-155G > T was curated as pathogenic. Conclusions: For the first time, a deep intronic mutation that was detected by NGS in the SERPING1 gene, was proven pathogenic for C1-INH-HAE. Therefore, advanced DNA sequencing methods should be performed in cases of C1-INH-HAE where standard approaches fail to uncover the genetic alteration.

AB - Background: In about 5% of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) no mutation in the SERPING1 gene is detected. Methods: C1-INH-HAE cases with no mutation in the coding region of SERPING1 after conventional genotyping were examined for defects in the intronic or untranslated regions of the gene. Using a next-generation sequencing (NGS) platform targeting the entire SERPING1, 14 unrelated C1-INH-HAE patients with no detectable mutations in the coding region of the gene were sequenced. Detected variants with a global minor allele frequency lower than the frequency of C1-INH-HAE (0.002%), were submitted to in silico analysis using ten different bioinformatics tools. Pedigree analysis and examination of their pathogenic effect on the RNA level were performed for filtered in variants. Results: In two unrelated patients, the novel mutation c.-22-155G > T was detected in intron 1 of the SERPING1 gene by the use NGS and confirmed by Sanger sequencing. All bioinformatics tools predicted that the variant causes a deleterious effect on the gene and pedigree analysis showed its co-segregation with the disease. Degradation of the mutated allele was demonstrated by the loss of heterozygosity on the cDNA level. According to the American College of Medical Genetics and Genomics 2015 guidelines the c.-22-155G > T was curated as pathogenic. Conclusions: For the first time, a deep intronic mutation that was detected by NGS in the SERPING1 gene, was proven pathogenic for C1-INH-HAE. Therefore, advanced DNA sequencing methods should be performed in cases of C1-INH-HAE where standard approaches fail to uncover the genetic alteration.

KW - C1-inhibitor deficiency

KW - Hereditary angioedema

KW - Intronic mutations

KW - Next-generation sequencing

KW - SERPING1 gene

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