HAE Diagnostic and Genetic Tests
Written by Margaret Anne Rockwood | Last updated September 8th, 2026
Medically reviewed by Timothy J. Craig, DO
Laboratory evaluation for hereditary angioedema (HAE) is essential, particularly because clinical manifestations of the disease overlap with other forms of angioedema. Blood tests measuring C1-INH function, C1-INH antigen levels and complement C4 are commonly used to evaluate suspected HAE 1 and 2. Genetic testing may also be used in certain cases, particularly when HAE with normal C1 inhibitor (C1-INH) is suspected.
The World Allergy Organization/European Academy of Allergy and Clinical Immunology (WAO/EAACI) guidelines for the classification, diagnosis, and treatment of HAE provide recommendations on testing strategies.
Clinical Presentation
HAE is characterized by recurrent, self-limited attacks of localized edema that develops over several hours. Attacks generally resolve within 2 to 5 days if untreated and within 24 hours if properly treated.
Unlike allergic angioedema, HAE attacks are not associated with urticaria or generalized pruritus.
The most commonly affected sites include:
- extremities (hands, feet, arms, legs)
- face
- lips and tongue
- genital region
- gastrointestinal tract
- upper airway (larynx)
Swelling is often asymmetric and may involve different anatomic sites sequentially or concurrently during an attack.
In individuals with deficient or dysfunctional C1-INH, the normal “brake” on the contact (ie, kallikrein–kinin) pathway is impaired, so relatively minor stimuli can sometimes produce disproportionate bradykinin generation and trigger an attack.
Most triggers transiently activate the contact/inflammatory system or cause local tissue injury, which increases factor XII and kallikrein activation. ACE inhibitors can trigger HAE attacks by impairing the degradation of bradykinin.
Laboratory Tests
HAE type I results from reduced levels and function of C1-INH, whereas type II is characterized by normal or elevated C1-INH levels but impaired C1-INH function. The distinction is primarily biochemical. Both forms may be caused by pathogenic variants in SERPING1 and symptoms, alongside disease severity, tend to overlap.
The WAO/EAACI recommends a lab panel that assesses C1-INH functional activity, C1-INH antigenic level, and complement C4. Combined results provide a high degree of diagnostic accuracy.
C4 is typically reduced in HAE-C1-INH, but normal C4 does not reliably exclude HAE, and C4 should not be used as the sole screening or diagnostic test.
Table I. HAE and Characteristic Laboratory Patterns for Diagnosis.
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| HAE subtype | C1-INH function | C1-INH antigen | C4 |
| HAE Type I | ↓ | ↓ | ↓ |
| HAE Type II | ↓ | Normal or ↑ | ↓ |
| HAE with normal C1-INH* | Normal | Normal | Typically normal |
*Note: Normal C1-INH and C4 results do not by themselves establish HAE-nC1-INH.
If results are abnormal, testing should be repeated for confirmation. Notably, testing during an HAE attack may increase the sensitivity of C4 measurement.
Hereditary or Acquired
In patients with later-onset C1-INH deficiency and disease, particularly after age 40 and especially if they have no family history, C1q can help distinguish hereditary disease from acquired C1-INH deficiency.
This differential can be investigated by measuring C1q, a protein component of the complement system that plays a key role in the innate immune system. C1q is often reduced in 75% of acquired angioedema cases, but generally normal in HAE.
Genetic Tests and SERPING1 Variants
Types I and II HAE are caused by pathogenic variants in SERPING1, which encodes C1-INH. Therefore, genetic testing is not routinely needed when a diagnosis is clearly established by lab tests.
Genetic testing is warranted to resolve equivocal findings or provide genetic confirmation for family evaluation.
Genetic testing is most useful when:
- C1-INH antigen and function are normal despite a convincing HAE phenotype.
- Biochemical findings are borderline, discordant, or otherwise difficult to interpret
- Molecular confirmation is needed to facilitate family screening, particularly when the familial pathogenic variant is known and in prenatal, neonatal, or otherwise equivocal cases.
- A de novo mutation, mosaicism, or unusual inheritance pattern is suspected.
- Prenatal or other specialized genetic counseling is being considered.
Genetic results should be interpreted in the context of the phenotype and biochemical findings, ideally incorporating a geneticist’s expertise.
HAE with C1-INH Deficiency/Dysfunction
SERPING1 encodes C1-INH. More than 900 SERPING1 variants have been reported, including missense, nonsense, frameshift, and splice variants as well as large deletions and duplications.
When genetic confirmation is appropriate, testing may include:
- Sanger sequencing or targeted next-generation sequencing (NGS): These methods identify single-nucleotide variants and small insertions/deletions across SERPING1 coding exons and exon-intron boundaries.
- Deletion/duplication analysis: If sequencing is negative, multiplex ligation-dependent probe amplification (MLPA) or comparable copy-number analysis can identify larger exon or whole-gene deletions/duplications that routine sequencing may miss. Studies combining sequencing with MLPA demonstrate the substantial allelic heterogeneity of SERPING1.
- Expanded SERPING1 sequencing: May be considered for rare cases with convincing biochemical HAE who have no variant detected by conventional exon sequencing. NGS covering intronic and untranslated regions can identify deep intronic pathogenic variants missed by standard testing.
HAE with Normal C1-Inhibitor (HAE-nC1-INH)
Genetic testing becomes considerably more important when the patient has recurrent angioedema that is strongly suggestive of HAE, but has normal C1-INH antigen and function. This is because standard biochemical testing cannot confirm HAE with normal C1-INH. In these patients, C1-INH antigen and function are normal and C4 may also be normal; therefore, identification of a recognized pathogenic variant can provide the key laboratory evidence establishing a specific HAE-nC1-INH subtype.
For suspected HAE with normal C1-INH, the WAO/EAACI guideline recommends testing such patients for known HAE-associated mutations.
When a reliable, specialized assay is available, this is commonly used as a first, discrete step. However, laboratories increasingly use targeted multigene NGS panels instead of sequential single-gene testing.
Currently recognized HAE-nC1-INH–associated genes include F12, PLG, ANGPT1, KNG1, MYOF and HS3ST6; more recently, pathogenic variants in CPN1 and DAB2IP have also been associated with hereditary recurrent angioedema and are included in the 2025 WAO classification.
These panels may also include SERPING1 and other genes involved in the kallikrein-kinin, endothelial-barrier, or angioedema pathways. Targeted NGS allows simultaneous assessment of multiple HAE-associated genes and can be more efficient than sequential Sanger sequencing when the phenotype does not identify an obvious molecular subtype.
Importantly, a negative panel does not necessarily exclude HAE-nC1-INH. Many clinically convincing family histories still lack an identifiable pathogenic variant, and additional HAE-associated genes continue to be characterized. In these cases, the clinician should return to the clinical diagnosis: confirm recurrent angioedema without urticaria, exclude medication-related and mast-cell–mediated angioedema, document family history when present, and consider failure to respond to histamine and mast cell inhibitors and response to bradykinin-targeted therapy as supportive evidence.
A final caveat: a variant of uncertain significance should not by itself establish an HAE diagnosis. Patients who meet clinical criteria but lack an identifiable mutation may be classified as having “HAE of unknown genetic cause (HAE-UNK)” and followed as knowledge of additional pathogenic variants evolves.
Sources
- Germenis AE, Margaglione M, Pesquero JB, et al. International consensus on the use of genetics in the management of hereditary angioedema. J Allergy Clin Immunol Pract. 2020;8(3):901-911. doi:10.1016/j.jaip.2019.10.005
- López-Lera A, Garrido S, Roche O, López-Trascasa M. SERPING1 mutations in 59 families with hereditary angioedema. Mol Immunol. 2011;49(1-2):18-27. doi:10.1016/j.molimm.2011.07.010
- Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema—The 2021 revision and update. Allergy. 2022;77(7):1961-1990. doi:10.1111/all.15214
- Vázquez DO, Giavina-Bianchi P, Josviack D, et al. The 2025 WAO guidelines for the classification, diagnosis, and treatment of hereditary angioedema, with consideration of worldwide disparities. World Allergy Organ J. 2026;19(5):101335. Published March 19, 2026. doi:10.1016/j.waojou.2026.101335
- Vatsiou S, Zamanakou M, Loules G, et al. A novel deep intronic SERPING1 variant as a cause of hereditary angioedema due to C1-inhibitor deficiency. Allergol Int. 2020;69(3):443-449. doi:10.1016/j.alit.2019.12.006
- Veronez CL, da Silva ED, Teixeira PVL, et al. Genetic analysis of hereditary angioedema in a Brazilian family by targeted next generation sequencing. Biol Chem. 2016;397(4):315-322. doi:10.1515/hsz-2015-0287
- Wang X, Lei S, Xu Y, Liu S, Zhi Y. Mutation update of SERPING1 related to hereditary angioedema in the Chinese population. Hereditas. 2022;159(1):28. doi:10.1186/s41065-022-00247-2
- Zuraw BL, Bork K, Bouillet L, et al. Hereditary angioedema with normal C1 inhibitor: an updated international consensus paper on diagnosis, pathophysiology, and treatment. Clin Rev Allergy Immunol. 2025;68(1):24. doi:10.1007/s12016-025-09027-4