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

Vatsiou, Sofia; Ζαμανάκου, Μαρία; Loules, Gedeon; Psarros, Fotis; Parsopoulou, Faidra; Csuka, Dorottya; Valerieva, Anna; Staevska, Maria; Porębski, Grzegorz; Obtułowicz, Krystyna; Magerl, Markus; Maurer, Marcus; Speletas, Matthaios; Germenis, Anastasios E.

doi:10.1016/j.alit.2019.12.009

Cited by 19 publications

(21 citation statements)

References 50 publications

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“…Chinese carrying the T nucleotide did not display an increased risk for diabetic retinopathy relative to WT (C) [78]. European and Mediterranean's carrying the T nucleotide did not display an increased risk for hereditary angioedema relative to WT (C) [71].…”

Section: Nm_0000622: C52-696c>tmentioning

confidence: 80%

“…European and Mediterranean patients carrying the T nucleotide failed to show a greater association with hereditary angioedema relative to WT (C) [71].…”

Section: Nm_0000622: C685+1100c>tmentioning

confidence: 87%

“…The intronic polymorphism 1030 +1975G>C has no pathogenic influence on hereditary angioedema although predicted as pathogenic [71].…”

Section: Nm_0000622: C1030-1975g>cmentioning

confidence: 98%

“…European and Mediterranean patients carrying the T nucleotide failed to show a greater association with hereditary angioedema relative to WT (G) [71]. Chinese Han carrying the T nucleotide did not depict a greater association with polypoidal choroidal vasculopathy relative to WT (G) [74].…”

Section: Nm_0000622: C1029+926g>tmentioning

confidence: 99%

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Potential impact on coagulopathy of gene variants of coagulation related proteins that interact with SARS-CoV-2

Holcomb

Alexaki

Hernandez

et al. 2020

Preprint

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Thrombosis has been one of the complications of the Coronavirus disease of 2019 (COVID-19), often associated with poor prognosis. There is a well-recognized link between coagulation and inflammation, however, the extent of thrombotic events associated with COVID-19 warrants further investigation. Poly(A) Binding Protein Cytoplasmic 4 (PABPC4), Serine/Cysteine Proteinase Inhibitor Clade G Member 1 (SERPING1) and Vitamin K epOxide Reductase Complex subunit 1 (VKORC1), which are all proteins linked to coagulation, have been shown to interact with SARS proteins. We computationally examined the interaction of these with SARS-CoV-2 proteins and, in the case of VKORC1, we describe its binding to ORF7a in detail. We examined the occurrence of variants of each of these proteins across populations and interrogated their potential contribution to COVID-19 severity. Potential mechanisms by which some of these variants may contribute to disease are proposed. Some of these variants are prevalent in minority groups that are disproportionally affected by severe COVID-19. Therefore, we are proposing that further investigation around these variants may lead to better understanding of disease pathogenesis in minority groups and more informed therapeutic approaches.Author summaryIncreased blood clotting, especially in the lungs, is a common complication of COVID-19. Infectious diseases cause inflammation which in turn can contribute to increased blood clotting. However, the extent of clot formation that is seen in the lungs of COVID-19 patients suggests that there may be a more direct link. We identified three human proteins that are involved indirectly in the blood clotting cascade and have been shown to interact with proteins of SARS virus, which is closely related to the novel coronavirus. We examined computationally the interaction of these human proteins with the viral proteins. We looked for genetic variants of these proteins and examined how these variants are distributed across populations. We investigated whether variants of these genes could impact severity of COVID-19. Further investigation around these variants may provide clues for the pathogenesis of COVID-19 particularly in minority groups.

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Section: Nm_0000622: C52-696c>tmentioning

confidence: 80%

“…European and Mediterranean patients carrying the T nucleotide failed to show a greater association with hereditary angioedema relative to WT (C) [71].…”

Section: Nm_0000622: C685+1100c>tmentioning

confidence: 87%

“…The intronic polymorphism 1030 +1975G>C has no pathogenic influence on hereditary angioedema although predicted as pathogenic [71].…”

Section: Nm_0000622: C1030-1975g>cmentioning

confidence: 98%

Section: Nm_0000622: C1029+926g>tmentioning

confidence: 99%

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Potential impact on coagulopathy of gene variants of coagulation related proteins that interact with SARS-CoV-2

Holcomb

Alexaki

Hernandez

et al. 2020

Preprint

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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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Deep Intronic SERPING1 Gene Variants: Ending One Odyssey and Starting Another?

et al. 2020

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

Cited by 19 publications

References 50 publications

Potential impact on coagulopathy of gene variants of coagulation related proteins that interact with SARS-CoV-2

Potential impact on coagulopathy of gene variants of coagulation related proteins that interact with SARS-CoV-2

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

Deep Intronic SERPING1 Gene Variants: Ending One Odyssey and Starting Another?

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