Targeted next-generation sequencing for the molecular diagnosis of hereditary angioedema due to C1-inhibitor deficiency

Loules, Gedeon; Ζαμανάκου, Μαρία; Parsopoulou, Faidra; Vatsiou, Sofia; Psarros, Fotis; Csuka, Dorottya; Porębski, Grzegorz; Obtułowicz, Krystyna; Valerieva, Anna; Staevska, Maria; López-Lera, Alberto; López-Trascasa, Margarita; Moldovan, Dumitru; Magerl, Markus; Maurer, Marcus; Speletas, Matthaios; Farkas, Henriette; Germenis, Anastasios E.

doi:10.1016/j.gene.2018.05.029

Cited by 38 publications

(31 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A good example is given by Ebo et al () with genetic investigations of SERPING1 and SNPs on peripheral and gonadal parent samples, in addition to the samples of index case and her sister. On the other hand, when applied to multiple alleles, next‐generation sequencing can ascertain the abundance of allele combinations (Loules et al, ; Veronez et al, ). Its precise incidence would be more systematically addressed by investigating the group of de novo variants.…”

Section: Discussionmentioning

confidence: 99%

“…Using MLPA could result in a false‐negative rate. Very recently, a precise mapping with identification of boundaries of multiexon deletion or duplication has been developed and standardized using a targeted next‐generation sequencing platform (Loules et al, ), an exon quantitation technique (EQT; Nicolicht et al, ) or a combination of MLPA and direct sequencing of boundaries (Wong, Wong, Au, & Chan, ). This accurate identification of 5′ and 3′ boundaries specifically establishes a deletion/duplication variant that differs or not from each other.…”

Section: Variants Of Serping1 In C1‐inhibitor Deficiencymentioning

confidence: 99%

See 1 more Smart Citation

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes

Ponard¹,

Gaboriaud

Charignon

et al. 2019

Human Mutation

View full text Add to dashboard Cite

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 This update documents 748 different SERPING1 variants, including published variants and additional 120 unpublished ones.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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…The clinical presentation of HAE type I and II is identical. In classic HAE with C1INH deficiency, more than 95% of patients have a mutation in SERPING1 which encodes C1INH [20, 80]. SERPING1 is an unstable gene due to a high incidence of Alu repeat sequences and CpG sites [20].…”

Section: Pathophysiology and Molecular Genetic Backgroundmentioning

confidence: 99%

“…In classic HAE with C1INH deficiency, more than 95% of patients have a mutation in SERPING1 which encodes C1INH [20, 80]. SERPING1 is an unstable gene due to a high incidence of Alu repeat sequences and CpG sites [20]. More than 500 mutations in the SERPING1 gene have been identified to date [81].…”

Section: Pathophysiology and Molecular Genetic Backgroundmentioning

confidence: 99%

“…It was not until 1963, however, that the pathophysiological background was clarified, when Virginia Donaldson and Richard Evans discovered the lack of C1 inhibitor (C1INH) in patients with HAE [17]. These patients have heterozygous mutations in SERPING1 encoding C1INH [18-20]. Almost 10 years later, an acquired form of C1INH deficiency (AAE) was identified [21].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hereditary Angio-Oedema for Dermatologists

Bygum¹

2019

Dermatology

View full text Add to dashboard Cite

Among angio-oedema patients, hereditary angio-oedema (HAE) should not be overlooked. Besides skin swellings, these patients might have very painful abdominal attacks and potentially life-threatening angio-oedema of the upper airway. They will not respond to traditional anti-allergic therapy with antihistamines, corticosteroids, and adrenaline, and instead need specific drugs targeting the kallikrein-kinin pathway. Classically, patients with HAE have a quantitative or qualitative deficiency of the C1 inhibitor (C1INH) due to different mutations in SERPING1, although a new subtype with normal C1INH has been recognised more recently. This latter variant is diagnosed based on clinical features, family history, or molecular genetic testing for mutations in F12, ANGPT1,or PLG.The diagnosis of HAE is often delayed due to a general unfamiliarity with this orphan disease. However, undiagnosed patients are at an increased risk of unnecessary surgical interventions or life-threatening laryngeal swellings. Within the last decade, new and effective therapies have been developed and launched for acute and prophylactic therapy. Even more drugs are under evaluation in clinical trials. It is therefore of utmost importance that patients with HAE are diagnosed as soon as possible and offered relevant therapy with orphan drugs to reduce morbidity, prevent mortality, and improve quality of life.

show abstract

Application of a dried blood spot based proteomic and genetic assay for diagnosing hereditary angioedema

Iuraşcu,

Balla,

Pereira

et al. 2023

Clinical & Translational All

Self Cite

View full text Add to dashboard Cite

BackgroundHereditary angioedema (HAE) with C1‐inhibitor deficiency (C1‐INH‐HAE) is a rare disease caused by low level (type I) or dysfunction (type II) of the C1‐inhibitor protein with subsequent reduction of certain complement protein levels.MethodsTo develop and test the reliability of a two‐tier method based on C1‐INH and C4 quantitation followed by genetic analysis from dried blood spot (DBS) for establishing the diagnosis of C1‐INH‐HAE. C1‐INH and C4 proteins have been quantified in human plasma using a classical immuno‐assay and in DBS using a newly developed proteolytic liquid chromatography–mass spectrometry method. Genetic analysis was carried out as reported previously (PMID: 35386643) and by a targeted next‐generation sequencing panel, multiplex ligation‐dependent probe amplification and in some cases whole genome sequencing.ResultsDBS quantification of C1‐INH and C4 showed the same pattern as plasma, offering the possibility of screening patients with AE symptoms either locally or remotely. Genetic analysis from DBS verified each of the previously identified SERPING1 mutations of the tested C1‐INH‐HAE patients and revealed the presence of other rare variations in genes that may be involved in the pathogenesis of AE episodes.ConclusionsC1‐INH/C4 quantification in DBS can be used for screening of hereditary AE and DNA extracted from dried blood spots is suitable for identifying various types of mutations of the SERPING1 gene.

show abstract

Targeted next-generation sequencing for the molecular diagnosis of hereditary angioedema due to C1-inhibitor deficiency

Cited by 38 publications

References 36 publications

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes

Hereditary Angio-Oedema for Dermatologists

Application of a dried blood spot based proteomic and genetic assay for diagnosing hereditary angioedema

Contact Info

Product

Resources

About