A catalog of the genetic causes of hereditary angioedema in the Canary Islands (Spain)

Abstract

Hereditary angioedema (HAE) is a rare disease where known causes involve C1 inhibitor dysfunction or dysregulation of the kinin cascade. The updated HAE management guidelines recommend performing genetic tests to reach a precise diagnosis. Unfortunately, genetic tests are still uncommon in the diagnosis routine. Here, we characterized for the first time the genetic causes of HAE in affected families from the Canary Islands (Spain). Whole-exome sequencing data was obtained from 41 affected patients and unaffected relatives from 29 unrelated families identified in the archipelago. The Hereditary Angioedema Database Annotation (HADA) tool was used for pathogenicity classification and causal variant prioritization among the genes known to cause HAE. Manual reclassification of prioritized variants was used in those families lacking known causal variants. We detected a total of eight different variants causing HAE in this patient series, affecting essentially SERPING1 and F12 genes, one of them being a novel SERPING1 variant (c.686-12A>G) with a predicted splicing effect which was reclassified as likely pathogenic in one family. Altogether, the diagnostic yield by assessing previously reported causal genes and considering variant reclassifications according to the American College of Medical Genetics guidelines reached 66.7% (95% Confidence Interval [CI]: 30.1-91.0) in families with more than one affected member and 10.0% (95% CI: 1.8-33.1) among cases without family information for the disease. Despite the genetic causes of many patients remain to be identified, our results reinforce the need of genetic tests as first-tier diagnostic tool in this disease, as recommended by the international WAO/EAACI guidelines for the management of HAE.

Keywords: genetic cause; hereditary angioedema; precision medicine; rare disease; variant interpretation.

Figure 1

Schematic representation of the steps followed for patient DNA sequencing data. Algorithms are shown in orange and processed files in blue. The HAE causal variants prioritized by HADA and the Sanger validation step are shown in green.

Figure 2

Pedigrees of unrelated HAE families in the Canary Islands.

Figure 3

IGV view of sequencing reads supporting each allele of SERPING1 variant (up), and Sanger sequencing validation showing both alleles (down).

Figure 4

Pedigree of HAE affected family without previously reported causal variant (A) and representation generated by SQUIRLs of predicted acceptor site for the novel SERPING1 c.686-12A>G affecting splice variant (B).