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 The Ambry Test HAE AMPLIFIED™ is designed to detect mutations in the SERPING1 gene known to cause HAE Type I and Type II.

TESTING BENEFITS & INDICATIONS
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 clinical manifestations are present.

TEST DESCRIPTION
This Ambry Test is a gene sequence analysis performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for 5’UTR as well as coding exons 2-8 of the SERPING1 gene, plus at least 20 bases into the 5’ and 3’ ends of all the introns. If no mutation is detected, analysis for gross deletions/duplications of the SERPING1 gene is performed by the Multiplex Ligation-Dependent Probe Amplification (MLPA) kit, developed by MRC Holland.  Specific mutation analysis for individual SERPING1 mutations known to be in the family is also available.

MUTATION DETECTION RATE
Mutations in the SERPING1 gene have been associated with ~82% of clinically affected HAE patients.⁴ The Ambry Test: HAE AMPLIFIED (SERPING1) is designed and validated to be capable of detecting ~98% of described mutations in SERPING1 gene for HAE Types I and II.

SPECIMEN REQUIREMENTS
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Send 20 µg in TE at 50-100 ng/µl. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.

REFERENCES
¹ Nzeako UC et al. Arch Intern Med. 2001;161:2417-2429.
² Zuraw BL. N Engl J Med 2008;359:1027-36.
³ Jensen NF et al. Anesth Analg. 1998;87:480-8.
⁴ Gosswein T et al. Cytogenet Genome Res 2008; 121:181-188.
⁵ Bork K et al. The Lancet 2000;365(9225):213-217.