Hereditary Angioedema via the SERPING1 /C1NH Gene

Hereditary angioedema (HAE) is a disorder affecting 1 in 50,000 people in the United States. It is characterized by recurrent episodes of angioedema occurring most frequent in skin and mucosal tissues including the upper respiratory and gastrointestinal tracts. A hallmark of HAE is angioedema without urticarial or pruritus and unresponsiveness to antihistamine therapy. The precise event triggering the non-inflammatory angioedema attacks is unclear, but episodes are self-limiting and typically last longer than 12 hours. Other symptoms include recurrent abdominal pain and laryngeal edema. In severe cases, laryngeal swelling may cause asphyxiation and death (Caccia et al. 2014; Cicardi et al. 2014). Mean age of onset is 11 years old, but symptoms may present at birth (Bork et al. 2006). There are three types of HAE. Types I and II are due to mutations in the SERPING1/C1NH gene and represent ~85% and 15% of cases, respectively. Type I HAE individuals have decreased C1INH (Complement 1 inhibitor) levels and activity compared to type II individuals only displaying impaired activity. Type III HAE is a rare disorder with some cases being due to mutations in the F12 gene (Caccia et al. 2014; Cicardi et al. 2014). Genetic testing is helpful in diagnosis of HAE in children younger than one year of age as C1INH levels and function are difficult to interpret and may lead to false positive or negative results (Nielsen et al. 1994). Genetic testing is also helpful in the differential diagnosis of HAE from acquired angioedema, allergic reactions with anaphylaxis, thyroid disorders, trichinosis, and autoimmune conditions such as systemic lupus (Cicardi et al 2014).

Type I and II HAE are inherited in an autosomal dominant manner through mutations in the SERPING1 gene. In rare cases, homozygous deficient patients have been described. In a study of 87 Spanish individuals with either type I or II HAE, missense, short insertions or deletions, nonsense, large deletions or insertions, and splicing variants represented 32%, 19%, 15%, and 11% of causative variants and occurred throughout the gene (Roche et al. 2005). Similar frequencies have been observed in other large population studies of patients with HAE (Pappalardo et al. 2008; Bygum et al. 2011). Mutations in the SERPING1 gene are not fully penetrant with about 10% of heterozygous individuals being asymptomatic (Roche et al. 2005). De novo mutations occur in about a quarter of cases (Pappalardo et al. 2000). The SERPING1 gene encodes the C1-INH serine protease inhibitor, which is involved in regulation of the complement cascade, kallikrein and other serine proteases involved in coagulation. Excess bradykinin, a potent vasodilatory peptide, due to loss of C1-INH function is thought to be the primary cause of angioedema in HAE. However, the exact mechanism responsible for angioedema attacks is still unclear (Caccia et al. 2014).

In a study of 87 individuals with either type I or II HAE, causative variants in the SERPING1 gene were found in all cases (Roche et al. 2005). A separate study of 102 individuals with HAE found causative variants in the SERPING1 gene in 96 cases (Pappalardo et al 2008). Type III HAE is rare and represents <1% of all HAE cases (Caccia et al. 2014). Analytical sensitivity is ~80% as large deletions and insertions occur in about 20% of cases and are not detectable by sequencing (Roche et al. 2005).

This test provides full coverage of all coding exons of the SERPING1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).