Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation

Hujová, Pavla; Souček, Přemysl; Grodecká, Lucie; Grombiříková, Hana; Ravčuková, Barbora; Kuklı́nek, Pavel; Hakl, Roman; Litzman, Jiří; Freiberger, Tomáš

doi:10.1007/s10875-020-00753-2

Cited by 25 publications

(27 citation statements)

References 57 publications

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“…It is possible that we have missed mutations in promoter region and deep‐intronic regions of the SERPING1 gene and large mutations in these patients. Recently, a deep‐intronic novel pseudoexon activating mutation in intron 6 of SERPING1 gene has been reported in a family with HAE 67 . Therefore, some of the patients with HAE in this study may have this deep‐intronic mutation or a variant in promoter region of the gene.…”

Section: Discussionmentioning

confidence: 76%

Novel SERPING1 gene mutations and clinical experience of type 1 hereditary angioedema from North India

Jindal

Rawat

Kaur

et al. 2020

Pediatric Allergy Immunology

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Section: Discussionmentioning

confidence: 76%

Novel SERPING1 gene mutations and clinical experience of type 1 hereditary angioedema from North India

Jindal

Rawat

Kaur

et al. 2020

Pediatric Allergy Immunology

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“…Similarly, HADA uses GRCh37/hg19 coordinates, which is still considered to be the gold standard in clinical settings [ 42 ]. Despite the fact that HADA can report the existence of variants residing in introns near the key elements for splicing, as has been recently found for a type I HAE case [ 43 , 44 ], novel variants affecting function residing deep within intron positions will remain undetected. The main reason is the limited capacity of current algorithms to predict the pathogenic potential of deep intronic variants [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Interactive Web-Based Resource for Annotation of Genetic Variants Causing Hereditary Angioedema (HADA): Database Development, Implementation, and Validation

et al. 2020

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Background Hereditary angioedema is a rare genetic condition caused by C1 esterase inhibitor deficiency, dysfunction, or kinin cascade dysregulation, leading to an increased bradykinin plasma concentration. Hereditary angioedema is a poorly recognized clinical entity and is very often misdiagnosed as a histaminergic angioedema. Despite its genetic nature, first-line genetic screening is not integrated in routine diagnosis. Consequently, a delay in the diagnosis, and inaccurate or incomplete diagnosis and treatment of hereditary angioedema are common. Objective In agreement with recent recommendations from the International Consensus on the Use of Genetics in the Management of Hereditary Angioedema, to facilitate the clinical diagnosis and adapt it to the paradigm of precision medicine and next-generation sequencing–based genetic tests, we aimed to develop a genetic annotation tool, termed Hereditary Angioedema Database Annotation (HADA). Methods HADA is built on top of a database of known variants affecting function, including precomputed pathogenic assessment of each variant and a ranked classification according to the current guidelines from the American College of Medical Genetics and Genomics. Results HADA is provided as a freely accessible, user-friendly web-based interface with versatility for the entry of genetic information. The underlying database can also be incorporated into automated command-line stand-alone annotation tools. Conclusions HADA can achieve the rapid detection of variants affecting function for different hereditary angioedema types, and further integrates useful information to reduce the diagnosis odyssey and improve its delay.

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“…These are hardly detectable with a direct sequencing approach. Using NGS technology two pathogenic deep intronic variants have been detected: the c.-22- 155G > T located at intron 1 and the c.1029 + 384A > G located at intron 6 [ 22 , 23 , 24 ].…”

Section: Hereditary Angioedemamentioning

confidence: 99%

“…Conventional methods for genotyping of C1-INH-HAE patients do not allow the analysis of SERPING1 intronic regions. Recently, with a custom next-generation sequencing (NGS) platform, it has been possible to analyze SERPING1 in its full length and identify two pathogenic deep intronic variants: c.-22- 155G > T located at intron 1 and c.1029 + 384A > G located at intron 6 [ 22 , 23 ]. However, SERPING1 genotyping is not recommended for the diagnosis of C1-INH-HAE because C1-INH-HAE presents a great allelic heterogeneity, and biochemical C1-INH testing is cost-effective and reliable.…”

Section: Diagnostic Applications Of Genetic Biomarkersmentioning

confidence: 99%

The Genetics of Hereditary Angioedema: A Review

Santacroce

D’Andrea

Maffione

et al. 2021

JCM

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Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Mutations in SERPING1, the gene that encodes C1-INH (C1 esterase inhibitor), are responsible for the majority of cases of hereditary angioedema. C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes that are implicated in the cascades of bradykinin generation, which increases the vascular permeability and allows the flow of fluids into the extracellular space and results in angioedema. Moreover, a dominantly inherited disease has been described that has a similar clinical picture to C1-INH-HAE (Hereditary angioedema due to C1 inhibitor deficiency), but with normal C1-INH level and activity. This new type of HAE has no mutation in the SERPING1 gene and it is classified as nC1-INH-HAE (HAE with normal C1-INH). Currently mutations in six different genes have been identified as causing nC1-INH-HAE: factor XII (F12), plasminogen (PLG), angiopoietin 1 (ANGPT1), Kininogen 1 (KNG1), Myoferlin (MYOF), and heparan sulfate (HS)-glucosamine 3-O-sulfotransferase 6 (HS3ST6). In this review we aim to summarize the recent advances in genetic characterization of angioedema and possible future prospects in the identification of new genetic defects in HAE. We also provide an overview of diagnostic applications of genetic biomarkers using NGS technologies (Next Generation Sequencing).

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Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation

Cited by 25 publications

References 57 publications

Novel SERPING1 gene mutations and clinical experience of type 1 hereditary angioedema from North India

Novel SERPING1 gene mutations and clinical experience of type 1 hereditary angioedema from North India

Interactive Web-Based Resource for Annotation of Genetic Variants Causing Hereditary Angioedema (HADA): Database Development, Implementation, and Validation

The Genetics of Hereditary Angioedema: A Review

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