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Hereditary Angioedema via the SERPING1 /C1NH Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8425 SERPING1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8425SERPING181479 81479(x2) $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Megan Piazza, PhD, FACMG

Clinical Features and Genetics

Clinical Features

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).

Genetics

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).

Clinical Sensitivity - Sequencing with CNV PGxome

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).

Testing Strategy

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).

Indications for Test

Type I HAE candidates typically present with undetectable to 30% of normal C1INH levels. Type II HAE individuals have normal antigen levels, but impaired C1INH activity. During episodes of angioedema, bradykinin levels may be up to seven fold increased and C4 levels are decreased. Patients with HAE present with angioedema without urticarial and therefore do not respond to antihistamine therapy (Cicardi et al. 2014). Ideal candidates have a family history of HAE.

Gene

Official Gene Symbol OMIM ID
SERPING1 606860
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Hereditary Angioneurotic Edema AR, AD 106100

Citations

  • Bork K, Meng G, Staubach P, Hardt J. 2006. Hereditary Angioedema: New Findings Concerning Symptoms, Affected Organs, and Course. The American Journal of Medicine 119: 267–274. PubMed ID: 16490473
  • Bygum A, Fagerberg CR, Ponard D, Monnier N, Lunardi J, Drouet C. 2011. Mutational spectrum and phenotypes in Danish families with hereditary angioedema because of C1 inhibitor deficiency: Mutational spectrum and phenotypes in Danish patients with HAE. Allergy 66: 76–84. PubMed ID: 20804470
  • Caccia S, Suffritti C, Cicardi M. 2014. Pathophysiology of Hereditary Angioedema. Pediatric Allergy, Immunology, and Pulmonology 27: 159–163. PubMed ID: 25538858
  • Cicardi M, Aberer W, Banerji A, Bas M, Bernstein JA, Bork K, Caballero T, Farkas H, Grumach A, Kaplan AP, Riedl MA, Triggiani M, Zanichelli A, Zuraw B; HAWK under the patronage of EAACI (European Academy of Allergy and Clinical Immunology). 2014. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy 69: 602–616. PubMed ID: 24673465
  • Nielsen EW, Johansen HT, Holt J, Mollnes TE. 1994. C1 inhibitor and diagnosis of hereditary angioedema in newborns. Pediatric research 35: 184–187. PubMed ID: 8165053
  • Pappalardo E, Caccia S, Suffritti C, Tordai A, Zingale LC, Cicardi M. 2008. Mutation screening of C1 inhibitor gene in 108 unrelated families with hereditary angioedema: Functional and structural correlates. Molecular Immunology 45: 3536–3544. PubMed ID: 18586324
  • Pappalardo E, Cicardi M, Duponchel C, Carugati A, Choquet S, Agostoni A, Tosi M. 2000. Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema. Journal of Allergy and Clinical Immunology 106: 1147–1154. PubMed ID: 11112899
  • Roche O, Blanch A, Duponchel C, Fontán G, Tosi M, López-Trascasa M. 2005. Hereditary angioedema: The mutation spectrum of SERPING1/C1NH in a large Spanish cohort. Human Mutation 26: 135–144. PubMed ID: 15971231

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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