HEREDITARY ANGIOEDEMA

Hereditary angioedema (HAE), also known as C1 inhibitor (C1-INH) deficiency causes subcutaneous and submucosal edema in the skin, respiratory and gastrointestinal tracts. 

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Hereditary angioedema (HAE), also known as C1 inhibitor (C1-INH) deficiency causes subcutaneous and submucosal edema in the skin, respiratory and gastrointestinal tracts. 

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Disease Name 
Hereditary Angioedema
Disease Information 

Hereditary angioedema (HAE), also known as C1 inhibitor (C1-INH) deficiency, is a rare autosomal dominant condition. The prevalence of the disease has been estimated to be approximately 1 in 50,000,with no gender predominance and no known differences in prevalence among ethnic groups.2 HAE is characterized by the occurrence of subcutaneous and submucosal edema in any part of the skin, respiratory and gastrointestinal tracts. Edema is self-limited and more commonly occurs in the extremities. Abdominal pain, nausea and vomiting are the dominant symptoms in HAE due to constriction caused by edema of the intestinal wall and mesentery.2 Episodes of swelling may also involve the upper respiratory tract, including the tongue, pharynx and larynx. In HAE patients, laryngeal edema can be life threatening due to asphyxiation and it can occur at any age.2,3 Edema can be precipitated by minor trauma to the tissue, such as dental work, infection, certain drugs such as estrogen or angiotensin converting enzyme inhibitors, as well as emotional stress.3

HAE is caused by mutations in the SERPING1 gene (also known as C1NH), which codes for C1 inhibitor (C1-INH) protein.4 Two types of HAE that have been described according to C1-INH activity and levels. In HAE Type I, accounting for 80-85% of all patients, C1-INH protein quantity is decreased by nearly 35%.1,4 In HAE Type II, serum levels of the protein are normal or elevated, but activity is reduced. A third type, HAE III, is associated with possible X-linked dominant inheritance and has been seen primarily in women.1,2,5

Testing Benefits & Indication 

Genetic analysis can provide confirmation of a clinical diagnosis of HAE. Once a mutation is identified in a patient, testing of other family members can help identify carriers before the appearance of clinical symptoms.

Test Description 

Our HAE genetic testing includes next generation sequencing (NGS) and deletion/duplication analysis of the SERPING1 gene. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized kit and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes, followed by polymerase chain reaction (PCR) and NGS. Additional Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.6 This test targets detection of DNA sequence mutations in all coding domains, and well into the 5’ and 3’ ends of all the introns and untranslated regions. Gross deletion/duplication analysis is performed via multiplex ligation probe amplification (MLPA, MRC Holland).

Mutation Detection Rate 

Mutations in the SERPING1 gene have been associated with ~82% of patients clinically affected with HAE (clinical sensitivity). Ambry's SERPING1 analysis can detect >99.9% of described mutations in the gene, when present (analytical sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above in the quick links section at the top of this page.

Turnaround Time 
TEST CODE TECHNIQUE DAYS
2746 SERPING1 Gene Sequence Analysis and deletion/duplication  14-28 

 

Genes 
SERPING1
References 
  1. Nzeako UC et al. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161:2417-2429.
  2. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359:1027-36.
  3. Jensen NF et al. C1 esterase inhibitor deficiency, airway compromise, and anesthesia. Anesth Analg. 1998;87:480-8.
  4. Gosswein T et al. Mutational spectrum of the C1INH (SERPING1) gene in patients with hereditary angioedema. Cytogenet Genome Res. 2008; 121:181-188. 
  5. Bork K et al. Hereditary angioedema with normal C1-inhibitor activity in women. The Lancet. 2000;365(9225):213-217. 
  6. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.