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

Abstract

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 13 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 HAE patients 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 angioedema patients, the methods of detection of HAE causative variants, the variant pathogenicity curation, the genotyping of HAE patients 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.

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

“…At the moment, HADA integrates information from 450 SNVs and indels from 5 genes ( SERPING1 , F12 , PLG , ANGPT1 , and KNG1 ) that we classified as variants likely affecting function. While curating this information, we found that variant descriptions in HAE cases did not follow a standard [ 4 ], and many of the studies did not clearly declare the causality of the reported variants [ 35 , 39 ]. This situation helps to explain why up to 21.3% (n=96) of the simple bona fide variants affecting function continue to be reported as VUS in the best case.…”

“…As is the case for many other rare diseases, genetic testing in HAE has become an important step to reduce the diagnostic odyssey [ 40 ], increase the diagnostic yield, and tailor treatments [ 4 , 5 ]. The widespread adoption of NGS technology in clinical settings has led to the emergence of a wide variety of bioinformatics tools to assist and accelerate the detection and interpretation of associated genetic variants and their impact on disease risks.…”

“…In fact, in patients with normal levels and activity of C1-INH, genetic testing is recommended for the routine diagnosis of many HAE subtypes. Furthermore, according to Germenis et al [ 4 ] and the international consensus on genetic aspects of HAE, it is widely recognized that C4 and C1-INH plasma measurements can generate inconclusive results even in patients with genetic defects in C1-INH. Based on this, HADA will surely help practitioners to adapt to the NGS-based genetic screens of HAE cases.…”

“…Many original descriptions of the genetic studies in HAE did not clearly declare the causality of the reported variants, thereby increasing the difficulty to identify variants with effects on the disease as opposed to variants without a disease effect [ 4 ]. To facilitate the interpretation of HADA results, we imposed the following filters for a variant to be designated as a variant affecting function ( Figure 1 ): (1) variants described as pathogenic in HAEdb; (2) variants with unknown effects in HAEdb but predicted as pathogenic, likely pathogenic, or of uncertain significance (VUS) by VarSome, ClinVar, or InterVar (a flag will advise users in the case that contradictory classification information is reported for a variant); and (3) a reported minor allele frequency<1% in gnomAD, either on the overall sample or for non-Finish Europeans (because most of the genetic studies in HAE to date have focused on European families).…”

“…Therefore, delayed or ambiguous diagnoses are common, increasing the risk of patient morbidity and mortality [ 3 ]. With exceptions for particular subtypes, the recent international consensus guidelines recommend the use of genetic testing to reach a definitive HAE diagnosis in clinical practice [ 4 ]. However, with increasing recognition that the genetic cause of HAE is more complex than previously anticipated [ 5 ], the tasks involved in the identification of the genetic defect in each patient are increasingly demanding [ 6 ].…”