SERPING1 and F12 combined variants in a hereditary angioedema family

Charignon, Delphine; Ponard, D.; Gennes, C. De; Drouet, Christian; Ghannam, Arije

doi:10.1016/j.anai.2018.05.031

Cited by 7 publications

(7 citation statements)

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“…For example, the levels of angiotensin-converting enzyme (ACE) are largely influenced by the rare insertion/deletion polymorphism rs1799752 and in turn ACE activity in plasma inversely correlates with the severity of HAE-FXII ( Rigat et al, 1990 ; Charignon et al, 2014 ). Moreover, bradykinin-mediated HAE is a genetically complex disease and patients with combined pathogenic variants in the SERPING1 and F12 genes have been described ( Charignon et al, 2018 ) which further complicate management. In this regard, genotyping the c.-4T>C status may provide important information in order to help predict the severity of HAE, and moreover, it could be readily included in next generation sequencing platforms intended for HAE diagnosis.…”

Section: Discussionmentioning

confidence: 99%

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

et al. 2020

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Background Hereditary angioedema due to the Thr328Lys variant in the coagulation factor XII (HAE-FXII) affects mainly women in whom the symptomatology is dependent on high estrogen levels. Clinical variability and incomplete penetrance are challenging features that hinder the diagnosis and management of HAE-FXII. The c.-4T>C Kozak polymorphism is the only common variation accounting for FXII plasma levels and was previously shown to modify the course of HAE due to C1-Inhibitor deficiency. Objectives To assess the influence of the c.-4T>C polymorphism on disease expression in 39 Spanish HAE-FXII index patients. Methods The c.-4T>C polymorphism was sequenced by the standard Sanger method, and HAE severity was calculated according to the score by Cumming et al. (2003) The activation of the contact system was quantified by the kallikrein-like activity of plasma in chromogenic assays upon activation with high-molecular-weight dextran sulfate. Results The c.-4CC genotype was overrepresented in the studied cohort: 82% were CC-homozygous (expected frequency = 59%) and 18% were CT-heterozygous (expected frequency = 39%) ( p = 0.001). Patients with a c.-4CC genotype exhibited higher kallikrein-like activity (0.9659 ± 0.1136) than those with a c.-4TC genotype (0.7645 ± 0.1235) ( p = 0.024) or healthy donors. Moreover, the polymorphism influenced HAE-FXII severity score (c.-4CC = 4.43 ± 2.28 vs c.-4TC = 2.0 ± 1.15; p = 0.006) but not the degree of estrogen dependence or time until remission. Conclusion The c.-4T>C polymorphism is overrepresented in a Spanish HAE-FXII cohort and significantly influences the degree of contact system activation and the clinical severity of the disease.

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Section: Discussionmentioning

confidence: 99%

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

et al. 2020

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“…In addition to compound heterozygosity of different SERPING1 variants, a combination of a nonpathogenic SERPING1 variant and a variant in other HAE susceptibility genes can result in a severe C1‐INH‐HAE phenotype as shown by the following examples. (a) Combinations with other HAE susceptibility genes have been reported with a severe C1‐INH‐HAE phenotype, when SERPING1 variants are combined with c.‐46C/T genotype of the F12 gene ( rs1801020 ; MAF 0.472) (Bors et al, ; Speletas et al, ) and c.51+3A>G variant of the SERPING1 gene with c.1032C>A;p.(Thr309Lys)/(Thr328Lys) of the F12 gene (Charignon, Ponard, de Gennes, Drouet, & Ghannam, ). (b) In almost all symptomatic patients of a big pedigree presenting with C1Inh deficiency, multiple allele combinations have been identified with c.1369G>C;p.(Ala435Pro)/(Ala457Pro) variant of the SERPING1 gene and ACE [c.970C>T;p.(Arg324Trp)], ENPEP [c.638A>G;p.(Gln213Arg)], KLK1 [c.433G>C;p.(Glu145Gln) or c.556A>G;p.(Lys186Glu)], KLKB1 (c.428G>A;p.(Ser143Asn) or c.1679G>A;p.(Arg560Gln)], KNG1 (c.533T>C;p.(Met178Thr) or c.591T>G;p.(Ile197Met)], NOS3 (c.894T>G;p.(Glu298Asp) or c.2654G>T;p.(Arg885Met)], and PRCP (c.336A>T;p.(Glu112Asp)] alleles (Veronez et al, ).…”

Section: Variants Of Serping1 In C1‐inhibitor Deficiencymentioning

confidence: 99%

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes

Ponard¹,

Gaboriaud

Charignon

et al. 2019

Human Mutation

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C1 inhibitor (C1Inh) deficiency is responsible for hereditary angioedema (C1‐INH‐HAE) and caused by variants of the SERPING1/C1INH/C1NH gene. C1Inh is the major control of kallikrein–kinin system. C1Inh deficiency leads to its uncontrolled activation, with subsequent generation of the vasoactive peptide bradykinin. This update documents 748 different SERPING1 variants, including published variants and additional 120 unpublished ones. They were identified as heterozygous variants (n = 729), as homozygous variants in 10 probands and as compound heterozygous variants (nine combinations). Six probands with heterozygous variants exhibited gonadal mosaicism. Probands with heterozygous (n = 72) and homozygous (n = 1) variants were identified as de novo cases. Overall, 58 variants were found at positions showing high residue conservation among serpins, and have been referred to as a mousetrap function of C1Inh: reactive center loop, gate, shutter, breach, and hinge. C1Inh phenotype analysis identified dysfunctional serpin variants with failed serpin–protease association and a residual 105‐kDa species after incubation with target protease. Regarding this characteristic, in conditions with low antigenic C1Inh, 74 C1‐INH‐HAE probands presented with an additional so‐called intermediate C1‐INH‐HAE phenotype. The present update addresses a comprehensive SERPING1 variant spectrum that facilitates genotype–phenotype correlations, highlighting residues of strategic importance for serpin function and for identification of C1Inh deficiency as serpinopathy.

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“…EGR2 has been linked to migration of CD4+ T cells to lung and to blood eosinophil levels in asthma [ 41 – 43 ]. Indirectly perturbed genes near ATF3 and EGR2 in the network include C2 [ 44 – 46 ], SERPING1 [ 47 ], ZG16B [ 48 ], and CEACAM3 [ 49 ], all of which have been linked to immune response, asthma, or auto-immune diseases. PerturbNet provided new insights into the molecular characterization based on ATF3 -centered pathway for the known GWAS SNP whose functional role in asthma has not been fully elucidated.…”

Section: Resultsmentioning

confidence: 99%

Learning gene networks underlying clinical phenotypes using SNP perturbation

2020

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Availability of genome sequence, molecular, and clinical phenotype data for large patient cohorts generated by recent technological advances provides an opportunity to dissect the genetic architecture of complex diseases at system level. However, previous analyses of such data have largely focused on the co-localization of SNPs associated with clinical and expression traits, each identified from genome-wide association studies and expression quantitative trait locus mapping. Thus, their description of the molecular mechanisms behind the SNPs influencing clinical phenotypes was limited to the single gene linked to the co-localized SNP. Here we introduce PerturbNet, a statistical framework for learning gene networks that modulate the influence of genetic variants on phenotypes, using genetic variants as naturally occurring perturbation of a biological system. PerturbNet uses a probabilistic graphical model to directly model the cascade of perturbation from genetic variants to the gene network to the phenotype network along with the networks at each layer of the biological system. PerturbNet learns the entire model by solving a single optimization problem with an efficient algorithm that can analyze human genome-wide data within a few hours. PerturbNet inference procedures extract a detailed description of how the gene network modulates the genetic effects on phenotypes. Using simulated and asthma data, we demonstrate that PerturbNet improves statistical power for detecting disease-linked SNPs and identifies gene networks and network modules mediating the SNP effects on traits, providing deeper insights into the underlying molecular mechanisms.

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SERPING1 and F12 combined variants in a hereditary angioedema family

Cited by 7 publications

References 9 publications

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes

Learning gene networks underlying clinical phenotypes using SNP perturbation

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