International Consensus on the Use of Genetics in the Management of Hereditary Angioedema

doi:10.1016/j.jaip.2019.10.004

The Journal of Allergy and Clinical Immunology: In Practice

Volume 8, Issue 3, March 2020, Pages 901-911

https://doi.org/10.1016/j.jaip.2019.10.004 Get rights and content

Hereditary angioedema (HAE) is becoming much more genetically complex than was initially considered. Thus, the role of HAE genetics is expanding beyond research laboratories, and the genotyping of subjects suffering from HAE has become diagnostically indispensable in clinical practice. The synthesis and interpretation of the clinical and biochemical analyses to facilitate appropriate genetic test selection has thus also become significantly more complex. With this in mind, an international multidisciplinary group of 14 experts in HAE genetics and disease management was convened in October 2018. The objective was to develop clear, actionable, evidence- and consensus-based statements aiming to facilitate the communication between physicians treating patients with HAE and clinical geneticists, and thus promote the effective use of genetics in the management of the disease. Eleven consensus statements were generated, encompassing considerations regarding the clinical indications for genotyping patients with angioedema, the methods of detection of HAE-causative variants, the variant pathogenicity curation, the genotyping of patients with HAE in the clinic, and genetic counseling. These statements are intended both to guide clinicians and to serve as a framework for future educational and further genetic testing developments as the field continues to evolve rapidly.

Introduction

Hereditary angioedema (HAE) is a potentially fatal genetic disorder manifested clinically by episodes of nonpruritic and nonpitting swelling of the subcutaneous and/or submucosal tissues. The prototype HAE with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) caused by mutations of the SERPING1 gene encoding C1-INH is diagnosed biochemically by the detection of low antigenic and/or functional levels of C1-INH with HAE genetics generally considered not to be required for the diagnosis of C1-INH-HAE and being reserved for selected cases where results are ambiguous.¹ Furthermore, the description of HAE with normal C1-INH (nl-C1-INH-HAE) in 2000² rekindled interest for HAE genetic testing. As a result, novel sequence variants are increasingly detected not only for SERPING1 gene but also for a rapidly increasing number of genes that are associated with HAE.¹

At the same time, high-throughput sequencing technologies facilitate the detection of sequence variants whose effects on gene expression or protein function are unclear. Moreover, the various techniques in use for genotyping patients with HAE are not validated and the concordance between them is largely unknown. As a consequence, HAE genetic diagnosis has become much more complex and the establishment of the genetic defect underlying individual cases represents an increasingly challenging task.

As the reach of HAE genetics is expanding beyond research laboratories, the emerging key issue is which genetic testing is appropriate for any given patient with HAE and how this evidence can be used to inform medical management decisions. Thus, this consensus paper is primarily aimed at physicians treating patients with HAE to facilitate the communication between them and clinical geneticists and therefore the effective use of genetics in the management of the disease (Table I).

Section snippets

C1-INH-HAE genetics

Initially identified for its regulatory activity in the complement system, C1-INH (UniProt ID: P05155) is a plasma serine protease inhibitor (Serpin), which controls the complement pathway through inhibition of C1r, C1s, MASP1, MASP2, the contact system by inhibiting factor XII and plasma kallikrein, the intrinsic coagulation cascade through factor XI and thrombin inhibition, and the fibrinolytic system through plasmin and tissue-plasminogen activator inhibition.³ In the 1960s, biochemical

Methods

An international multidisciplinary group of 14 experts in HAE genetics and disease management was convened in 2018 and tasked with the development of an evidence- and consensus-based statement aiming to facilitate the communication between physicians treating patients with HAE and clinical geneticists and thus the effective use of genetics in the management of the disease. In October 2018, the group of experts held a preliminary meeting in Gazzada Schianno, Italy, where they identified 5 key

Statement 3

SERPING1 genotyping should cover all exonic, 5′- and 3′-untranslated regions and exon-intron boundaries for single-nucleotide variants, multinucleotide variants, and large defects.

Sanger sequencing is generally the most cost-effective and preferred technique when undertaking genetic screening of small, single genes such as SERPING1. However, high-throughput technologies are now available for massive DNA sequencing and are being successfully applied to SERPING1 screening.⁵⁴ Whole-exome

Variant Pathogenicity Curation

About a third of SERPING1 variants are not protein-truncating or misfolding missense mutations, most of which lack strong evidence regarding their pathogenicity. At the same time, only half of the nearly 600 HAE-associated SERPING1 variants found in the literature are reported in public databases, such as HAEdb and ClinVar, with not uncommon discordances among them. Moreover, information regarding variants of HAE-related genes that have been proved benign is missing from public databases.

Conclusions

The incorporation of new genetic findings from HAE research into clinical practice will be an ongoing challenge, as we expect the discovery of additional genes relevant to HAE. After the round table discussion on genetics of HAE of the 11th C1-INH Deficiency and Angioedema Workshop, HAE cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin was published.⁷⁶

This consensus document aims to define a structure to aid clinicians and geneticists

Acknowledgments

Hereditary Angioedema International Working Group members include: Sladjana Andrejevic, Serbia; Emel Aygören-Pürsün, Germany; Noemi-Anna Bara, Romania; Jonathan Bernstein, USA; Konrad Bork, Germany; Laurence Bouillet, France; Maria Bova, Italy; Henrik Halle Boysen, Denmark; Anette Bygum, Denmark; Teresa Caballero, Spain; Anthony Castaldo, USA; Sandra Christiansen, USA; Marco Cicardi, Italy; Jose Fabiani, Argentina; Connie Katelaris, Australia; Georg Dewald, Germany; Nihal M. Gökmen, Turkey;

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Hereditary angioedema with normal C1 inhibitor associated with carboxypeptidase N deficiency
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Hereditary angioedema (HAE) is a potentially life-threatening disorder characterized by recurrent episodes of subcutaneous or submucosal swelling. HAE with normal C1 inhibitor (HAE-nC1-INH) is an underdiagnosed condition. Although the association with genetic variants has been identified for some families, the genetic causes in many patients with HAE-nC1-INH remain unknown. The role of genes associated with bradykinin catabolism is not fully understood.
We sought to investigate the biological parameters and the genes related to kallikrein-kinin system in families with a clinical phenotype of HAE-nC1-INH and presenting with a carboxypeptidase N (CPN) deficiency.
This study includes 4 families presenting with HAE-nC1-INH and CPN deficiency. Patients’ clinical records were examined, biological parameters of kallikrein-kinin system were measured, and genetics was analyzed by next-generation sequencing and Sanger sequencing. Predictive algorithms (Human Splicing Finder, Sorting Intolerant From Tolerant, Polymorphism Phenotyping v2, MutationTaster, and ClinPred) were used to classify variants as affecting splicing, as benign to deleterious, or as disease-causing.
Patients presented with angioedema and urticaria, mainly on face/lips, but also with abdominal pain or laryngeal symptoms. Affected patients displayed low CPN activity—30% to 50% of median value in plasma. We identified 3 variants of the CPN1 gene encoding the catalytic 55-kDa subunit of CPN: c.533G>A, c.582A>G, and c.734C>T. CPN deficiency associated with genetic variants segregated with HAE-nC1-INH symptoms in affected family members.
CPN1 gene variants are associated with CPN deficiency and HAE-nC1-INH symptoms in 4 unrelated families. Genetic CPN deficiency may contribute to bradykinin and anaphylatoxin accumulation, with synergistic effects in angioedema and urticarial symptoms.
The US Hereditary Angioedema Association Scientific Registry: hereditary angioedema demographics, disease severity, and comorbidities
2023, Annals of Allergy, Asthma and Immunology
Hereditary angioedema (HAE) and idiopathic nonhistaminergic angioedema (INHA) are ultra-rare diseases whose natural histories and comorbidities are incompletely understood.
To develop a national patient-centric registry to address these deficiencies in our knowledge and improve our ability to assess the real-world impact of therapeutic interventions.
Data from members of the US HAE Association were collected into an online registry between 2009 and April 7, 2021. Cohorts were categorized by reported physician diagnosis. Patient reported data were collected using a series of questionnaires. Demographic, natural history, and family history outcomes of the HAE due to C1 inhibitor deficiency (HAE-C1INH) participants were compared with those of the combined HAE with normal C1 inhibitor (HAE-nl-C1INH) plus INHA group. The prevalence of comorbid conditions in the HAE-C1INH group was compared with the general US population.
A total of 485 HAE-C1INH, 26 HAE-nl-C1INH, and 70 INHA participants were included in the analysis. Delay to diagnosis was shorter in HAE-C1INH (5 vs 11 years), but both had decreasing delays over time. Differences in attack frequency and location were found between the groups. Morbidity surrogates including emergency department visits, hospitalizations, unnecessary abdominal surgeries, and intubations were strikingly high as was mortality with 36.9% of HAE-C1INH and 15.4% of HAE-nl-C1INH participants reporting family members who died from a HAE attack. Females with HAE-C1INH had a significant increase in the prevalence of depression, sleep disorders, kidney disease, anemia, and hepatitis. Cardiovascular comorbidities were significantly reduced in the HAE-C1INH group.
The US HAEA Scientific Registry provides a mechanism to enhance our knowledge of HAE and INHA.
The multifactorial impact of receiving a hereditary angioedema diagnosis
2023, World Allergy Organization Journal
Hereditary angioedema (HAE) is a rare, chronic, debilitating genetic disorder characterized by recurrent, unpredictable, and potentially life-threatening episodes of swelling that typically affect the extremities, face, abdomen, genitals, and larynx. The most frequent cause of HAE is a mutation in the serpin family G member 1 (SERPING1) gene, which either leads to deficient plasma levels of the C1-esterase inhibitor (C1–INH) protein (type I HAE-C1-INH) or normal plasma levels of dysfunctional C1–INH protein (type II HAE-C1-INH). Mutations in SERPING1 are known to be associated with dysregulation of the kallikrein-bradykinin cascade leading to enhancement of bradykinin production and increased vascular permeability. However, some patients present with a third type of HAE (HAE-nl-C1-INH) that is characterized by normal plasma levels and functionality of the C1–INH protein. While mutations in the factor XII, angiopoietin-1, plasminogen, kininogen-1, myoferlin, and heparan sulfate-glucosamine 3-O-sulfotransferase-6 genes have been identified in some patients with HAE-nI-C1-INH, genetic cause remains unknown in many cases with further research required to fully elucidate the pathology of disease in these patients. Here we review the challenges that arise on the pathway to a confirmed diagnosis of HAE and explore the multifactorial impact of receiving a HAE diagnosis. We conclude that it is important to continue to raise awareness of HAE because delays to diagnosis have a direct impact upon patient suffering and quality of life. Since many patients will seek help from hospitals during their first swelling attack it is vital that emergency department staff are aware of the different pathological pathways that distinguish HAE from other forms of angioedema to ensure that the most appropriate treatment is administered.
As disease awareness increases, it is hoped that patients will be diagnosed earlier and that pre-authorization and insurance coverage of HAE treatments will become easier to obtain, ultimately reducing the burden of treatment for these patients and their caregivers.
Hereditary Angioedema During Pregnancy: Considerations in Management
2023, Immunology and Allergy Clinics of North America
Citation Excerpt :
Before pregnancy, counseling potential parents on the genetic nature of HAE and the autosomal inheritance pattern is important so that families understand the risk of children inheriting the condition. For HAE-C1INH, the risk is 50% for each individual offspring when one parent is affected by HAE-C1INH.38 For HAE-nl-C1INH, the inheritance pattern also seems to be autosomal-dominant, although strong estrogen effects on symptom expression lead to males rarely being symptomatic.39
Differentiating histaminergic and nonhistaminergic angioedema with or without urticaria
2022, Journal of Allergy and Clinical Immunology
The international WAO/EAACI guideline for the management of hereditary angioedema – The 2021 revision and update
2022, World Allergy Organization Journal
Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2), by providing guidance on common and important clinical issues, such as: 1) How should HAE be diagnosed? 2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? 3) What are the goals of treatment? 4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast feeding women? 5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.

View all citing articles on Scopus

: Conflicts of interest: The authors declare that they have no relevant conflicts of interest.

^∗: See Acknowledgments at the end of the article for a list of the members of Hereditary Angioedema International Working Group.

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Review and Feature ArticleInternational Consensus on the Use of Genetics in the Management of Hereditary Angioedema

Introduction

Section snippets

C1-INH-HAE genetics

Methods

Statement 3

Variant Pathogenicity Curation

Conclusions

Acknowledgments

J Allergy Clin Immunol Pract

Lancet

Immunol Allergy Clin North Am

J Allergy

Am J Med

J Biol Chem

FEBS Lett

Clin Immunol

Lancet

J Allergy Clin Immunol

Mol Immunol

J Allergy Clin Immunol

Biochem Biophys Res Commun

Clin Immunol

Clin Immunol

Am J Hum Genet

J Allergy Clin Immunol

Blood

J Biol Chem

Biochem Biophys Res Commun

J Allergy Clin Immunol

World Allergy Organ J

Reprod Biomed Online

Gene

Gene

J Allergy Clin Immunol Pract

Clin Immunol

J Allergy Clin Immunol

Genet Med

Genet Med

Am J Hum Genet

Genet Med

J Allergy Clin Immunol

Molecular basis for the deficiency of complement 1 inhibitor in type I hereditary angioneurotic edema

J Clin Invest

Altered C1 inhibitor genes in type I hereditary angioedema

N Engl J Med

Type I C1 inhibitor deficiency with a small messenger RNA resulting from deletion of one exon

J Clin Invest

Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group

Allergy

Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema

J Clin Invest

Review and Feature Article
International Consensus on the Use of Genetics in the Management of Hereditary Angioedema