Home
HelpTest Code AHUGP Atypical Hemolytic Uremic Syndrome (aHUS)/Thrombotic Microangiopathy (TMA) /Complement 3 Glomerulopathy (C3G) Gene Panel, Varies
Ordering Guidance
Due to atypical hemolytic uremic syndrome genotype-phenotype complexity, targeted testing for familial variants will not be accepted without approval from the laboratory; call 800-533-1710 to discuss testing options with a genetic counselor.
Customization of this panel and single gene analysis for any gene present on this panel are available. For more information, see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies. To modify this panel via CGPH, use the Hereditary Renal Conditions disease state for step 1 on the Custom Gene Ordering Tool.
Shipping Instructions
Specimen Required
Patient Preparation: A previous hematopoietic stem cell transplant from an allogenic donor will interfere with testing. For information about testing patients who have received a hematopoietic stem cell transplant, call 800-533-1710.
Submit only 1 of the following specimens:
Specimen Type: Whole blood
Container/Tube: Lavender top (EDTA) or yellow top (ACD)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send whole blood specimen in original tube. Do not aliquot.
3. Whole blood collected postnatal from an umbilical cord is also acceptable. See Additional Information
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days
Additional Information:
1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.
2. To ensure minimum volume and concentration of DNA are met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.
3. For postnatal umbilical cord whole blood specimens, maternal cell contamination studies are recommended to ensure test results reflect that of the patient tested. A maternal blood specimen is required to complete maternal cell contamination studies. Order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on both the cord blood and maternal blood specimens under separate order numbers.
Specimen Type: Skin biopsy
Supplies: Fibroblast Biopsy Transport Media (T115)
Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin.
Specimen Volume: 4-mm Punch
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information: Specimen will only be tested after culture.
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks are required to culture fibroblasts before genetic testing can occur.
Specimen Type: Cultured fibroblasts
Source: Skin or tissue
Container/Tube: T-25 flask
Specimen Volume: 2 Flasks
Collection Instructions: Submit confluent cultured fibroblast cells from a skin or tissue biopsy.
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks are required to culture fibroblasts before genetic testing can occur.
Specimen Type: Extracted DNA
Container/Tube:
Preferred: Screw Cap Micro Tube, 2 mL with skirted conical base
Acceptable: Matrix tube, 1 mL
Collection Instructions:
1. The preferred volume is at least 100 mcL at a concentration of 75 ng/mcL.
2. Include concentration and volume on tube.
Specimen Stability Information: Frozen (preferred) 1 year/Ambient/Refrigerated
Additional Information: DNA must be extracted in a CLIA-certified laboratory or equivalent and must be extracted from a specimen type listed as acceptable for this test (including applicable anticoagulants). Our laboratory has experience with Chemagic, Puregene, Autopure, MagnaPure, and EZ1 extraction platforms and cannot guarantee that all extraction methods are compatible with this test. If testing fails, one repeat will be attempted, and if unsuccessful, the test will be reported as failed and a charge will be applied. If applicable, specific gene regions that were unable to be interrogated due to DNA quality will be noted in the report.
Prenatal Specimens
Due to its complexity, consultation with the laboratory is required for all prenatal testing; call 800-533-1710 to speak to a genetic counselor.
Specimen Type: Amniotic fluid
Container/Tube: Amniotic fluid container
Specimen Volume: 20 mL
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information: Specimen will only be tested after culture.
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULAF / Culture for Genetic Testing, Amniotic Fluid. An additional 2 to 3 weeks are required to culture amniotic fluid before genetic testing can occur.
3. All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Type: Confluent cultured amniocytes
This does not include cultured chorionic villi.
Container/Tube: T-25 flask
Specimen Volume: 2 Full flasks
Collection Instructions: Submit confluent cultured amniocytes from another laboratory.
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing.
3. All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Type: Chorionic villi
Container/Tube: 15-mL tube containing 15 mL of transport media
Specimen Volume: 20 mg
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information: Specimen will only be tested after culture.
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks are required to culture fibroblasts before genetic testing can occur.
3. All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Type: Cultured chorionic villi
Container/Tube: T-25 flasks
Specimen Volume: 2 Full flasks
Collection Instructions: Submit confluent cultured cells from another laboratory.
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing.
3. All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Forms
1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing-Spanish (T826)
2. Hereditary Renal Genetic Testing Patient Information (T918)
3. If not ordering electronically, complete, print, and send a Renal Diagnostics Test Request (T830) with the specimen.
Useful For
Providing a genetic evaluation for patients with a personal or family history suggestive of atypical hemolytic uremic syndrome (aHUS), thrombotic microangiopathy (TMA), or complement 3 glomerulopathy (C3G)
Establishing a diagnosis of genetic aHUS, TMA, or C3G and, in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved
Identifying variants in genes encoding complement alternate pathway components and specific coagulation pathway genes known to be associated with increased risk for aHUS, TMA, and C3G allowing for predictive testing of at-risk family members
Providing genetic information that may be considered when making treatment decisions, including duration of therapy and recurrence risk, as well as consideration of transplantation
Genetics Test Information
This test utilizes next-generation sequencing to detect single nucleotide, small deletion-insertion, and copy number variants in 15 genes associated with atypical hemolytic uremic syndrome (aHUS), thrombotic microangiopathy (TMA), and complement 3 glomerulopathy (C3G): ADAMTS13, C3, C5[Chr9(GRCh37):g.123759950-123759973 only], CD46 (MCP), CFB, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, DGKE, MMACHC, and THBD. See Targeted Genes and Methodology Details for Atypical Hemolytic Uremic Syndrome / Thrombotic Microangiopathy / Complement 3 Glomerulopathy Gene Panel in Method Description for additional details.
Identification of a pathogenic variant may assist with diagnosis, prognosis, clinical management, familial screening, and genetic counseling for aHUS, TMA, and C3G.
Reflex Tests
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| CULFB | Fibroblast Culture for Genetic Test | Yes | No |
| CULAF | Amniotic Fluid Culture/Genetic Test | Yes | No |
| MATCC | Maternal Cell Contamination, B | Yes | No |
Testing Algorithm
Prenatal specimens:
If an amniotic fluid specimen or cultured amniocytes are received, an amniotic fluid culture will be performed at an additional charge.
If a chorionic villi specimen or cultured chorionic villi are received, a fibroblast culture will be performed at an additional charge.
For any prenatal specimen that is received, maternal cell contamination testing will be performed at an additional charge.
Skin biopsy or cultured fibroblast specimens:
For skin biopsy or cultured fibroblast specimens, a fibroblast culture will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
Cord blood:
For cord blood specimens that have an accompanying maternal blood specimen, maternal cell contamination studies will be performed at an additional charge.
Special Instructions
Method Name
Sequence Capture and Amplicon-Based Next-Generation Sequencing (NGS)
Reporting Name
aHUS/TMA/C3G Gene PanelSpecimen Type
VariesSpecimen Minimum Volume
See Specimen Required
Specimen Stability Information
| Specimen Type | Temperature | Time |
|---|---|---|
| Varies | Varies | |
Reject Due To
All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.Clinical Information
Thrombotic microangiopathy (TMA) is a pathologic condition characterized by abnormalities in the walls of small blood vessels (arterioles and capillaries) that result in microvascular thrombosis. Typically, they feature microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, but these features may not be apparent in kidney-limited disease. Laboratory findings may include anemia, thrombocytopenia, presence of schistocytes on peripheral smear, elevated lactate dehydrogenase, and elevated serum creatinine.(1,2) The main categories of TMA include complement-mediated TMA (CM-TMA; also known as atypical hemolytic syndrome [aHUS]), thrombotic thrombocytopenic purpura (TTP), Shiga toxin-mediated hemolytic uremic syndrome, and drug-induced TMA. Due to the overlapping clinical features, laboratory testing is useful in differentiated these disorders.(3)
Complement-mediated thrombotic microangiopathy (CM-TMA) (aHUS) is a well-recognized disease entity characterized by complement activation in the microvasculature. Abnormalities of the alternate pathway of complement, which may be inherited (genetic) or acquired, underlie both the sporadic and familial forms of the disease and are identified estimated to occur in approximately 60% of affected individuals.(3,4) Unlike many other monogenic disorders of the immune system, multiple hits may be required for disease manifestation, which may include a trigger event (transplantation, pregnancy, malignant hypertension, autoimmune disorders, sepsis, malignancy, etc) and one or more contributing genetic variants or risk haplotypes in the alternate pathway complement genes.(3) Individuals with genetic CM-TMA (aHUS) may experience relapse even after complete recovery following the presenting episode.
Thrombotic thrombocytopenic purpura is a rare clinical entity but is important to diagnose properly since it is associated with very high mortality (90%) if untreated. Mortality can be reduced by early plasma exchange. Congenital TTP is due to genetic defects in the ADAMTS13 gene, while acquired TTP is related to autoantibodies against ADAMTS13, which reduces function. While TTP was initially characterized by thrombocytopenia, MAHA, fluctuating neurological signs, kidney failure and fever, not all of these features may be present in the manifestation of the disease.(1,2)
The hereditary form of CM-TMA is characterized by the presence of disease-causing variants in one or more of the genes known to be associated with aHUS, irrespective of familial history, or when two or more members of the same family are affected by the disease at least 6 months apart and exposure to a common triggering infectious agent has been excluded.(3) A patient may have both genetic variants in the alternative complement pathway and autoantibodies. While genetic testing may be used during the diagnostic work-up, the presence of disease-causing variants may also alter recurrence risk and impact decisions related to continuation of anti-complement therapy after resolution of symptoms.
Complement 3 glomerulopathies (C3G) include dense deposit disease and C3 glomerulonephritis and are characterized by C3 deposition within the glomeruli. In these disorders, the activity of the C3 convertase is increased by C3 nephritic factors, which are antibodies that stabilize the convertase, or loss of complement regulator activity, which may be due to genetic variants, autoantibodies, or other immunoglobulins. C3G may be preceded by an upper respiratory tract infection in some cases. Patients typically have proteinuria or hematuria and may present with variable kidney impairment. In addition to medical therapy, patients may be treated with kidney transplantation; however, disease recurrence and graft loss may occur.(4)
It is important to note that while TMA and C3G are associated with complement dysregulation, disease-causing variants in these genes may also result in complement deficiency, which is associated with recurrent infections with encapsulated pathogens or connective tissue diseases with no evidence of aHUS/TMA.(5)
Two risk alleles associated with increased susceptibility to aHUS/TMA and variants in C5 associated with poor response to anticomplement therapy are also included on this panel to aid in risk assessment:
-CFH-H3 risk haplotype: The variants that comprise this risk haplotype are common in the general population, but in the context of additional pathogenic genetic and environmental factors, the presence of this risk haplotype is associated with an increased risk for development or progression of atypical hemolytic uremic syndrome.(6)
-MCP/CD46 risk haplotype: The variants that comprise this risk haplotype are common in the general population, but in the context of additional pathogenic genetic and environmental factors, the presence of this risk haplotype is associated with an increased risk for development or progression of atypical hemolytic uremic syndrome.(6)
-C5 genotype: Two variants, p.Arg885His and p.Arg885Cys, have been associated with poor response to eculizumab.(7)
In addition, assessment of the CFHR gene cluster (CFHR1, CFHR2, CFHR3, CFHR4, and CFHR5) is included. Homozygous deletion of CFHR1 is enriched in patients with complement factor H (FH) autoantibodies (79%-89%), suggesting homozygous CFHR1 deletions may be a risk factor for FH autoantibody development.(8) However, variation, including simple variants and copy number variants, at this locus is common in the general population and at this time the clinical significance of other variants within this gene cluster is uncertain.
Reference Values
An interpretive report will be provided.
Interpretation
All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(9) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Day(s) Performed
Varies
Report Available
21 to 28 daysSpecimen Retention Time
Whole blood: 25 days (if available); Extracted DNA: 3 monthsPerforming Laboratory
Mayo Clinic Laboratories in Rochester
Test Classification
This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.CPT Code Information
81404
81479
81479 (if appropriate for government payers)
LOINC Code Information
| Test ID | Test Order Name | Order LOINC Value |
|---|---|---|
| AHUGP | aHUS/TMA/C3G Gene Panel | 99967-2 |
| Result ID | Test Result Name | Result LOINC Value |
|---|---|---|
| 618017 | Test Description | 62364-5 |
| 618018 | Specimen | 31208-2 |
| 618019 | Source | 31208-2 |
| 618020 | Result Summary | 50397-9 |
| 618021 | Result | 82939-0 |
| 618022 | Interpretation | 69047-9 |
| 618023 | Additional Results | 82939-0 |
| 618024 | Resources | 99622-3 |
| 618025 | Additional Information | 48767-8 |
| 618026 | Method | 85069-3 |
| 618027 | Genes Analyzed | 48018-6 |
| 618028 | Disclaimer | 62364-5 |
| 618029 | Released By | 18771-6 |