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Test Catalog

Test ID: AHUSP    
Complement-Mediated Atypical Hemolytic-Uremic Syndrome (aHUS)/Thrombotic Microangiopathy (TMA) Gene Panel, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of complement-mediated HUS/atypical HUS (aHUS) or thrombotic microangiopathies (TMA)

 

Establishing a diagnosis 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 allowing for predictive testing of at-risk family members

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes next-generation sequencing and supplemental Sanger sequencing to evaluate for the genes listed on the panel.

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

For skin biopsy or cultured fibroblast specimens, fibroblast culture and cryopreservation testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Complement-mediated hemolytic uremic syndrome, also known as atypical hemolytic uremic syndrome (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 in at least two-thirds (approximately 60%) of patients. 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 1 or more contributing genetic variants or haplotypes in the alternate pathway complement genes. The overall prognosis is poor with most patients developing end-stage renal disease (ESRD) or permanent kidney injury within 1 year of diagnosis despite plasma exchange (PLEX/PEX) or plasma infusion (PI) therapy. Renal transplantation in most patients is also associated with a poor prognosis with loss of the allograft. Drugs targeting the complement pathway, notably Eculizumab, have achieved success in modulating clinical remission and there are a few reports of combined liver-kidney transplants for these patients. Newer therapies are also likely to emerge over time. Individuals with genetic aHUS frequently experience relapse even after complete recovery following the presenting episode. Complement-mediated HUS presents with clinical features that are nearly identical to thrombotic thrombocytopenic purpura (TTP) and Shiga-toxin HUS (ST-HUS), making laboratory differentiation essential.

 

TTP is a rare clinical entity but is an important diagnosis as it is associated with very high mortality (90%) if untreated. Mortality can be reduced by early PLEX. 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, microangiopathic hemolytic anemia (MAHA), fluctuating neurological signs, renal failure and fever, the disease can present with only some of these features. The thrombotic microangiopathies (TMA) cover both aHUS and TTP and the clinical distinctions are not always clear-cut. Besides the thrombocytopenia, which is one of the key features of TMA, there is presence of schistocytes and highly increased levels of lactate dehydrogenase (LDH).

 

Complement-mediated HUS is considered genetic when 2 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, or when pathogenic variants are identified in 1 or more of the genes known to be associated with aHUS, irrespective of familial history. A patient may have both autoantibodies to complement alternate pathway proteins and genetic defects in these genes.

 

It is important to note that certain genetic defects in these genes, eg, complement C3 (C3), may be associated with a more classic immunodeficiency phenotype with recurrent infections with encapsulated pathogens and connective tissue diseases with no evidence of aHUS/TMA.

 

Table 1. Genes included in the Complement aHUS/TMA PID Gene Panel 

 

GENE SYMBOL (ALIAS)

PROTEIN

OMIM

INCIDENCE

INHER ITANCE

PHENOTYPE DISORDER

ADAMTS13

A disintegrin and metalloproteinase with thrombospondin motifs 13 isoform 1 preproprotein

604134

Not available

AR

Familial thrombotic thrombocytopenic purpura

C3

Complement C3 preproprotein

120700

Approximately 5% of aHUS

AD, AR

C3 deficiency (AR), susceptibility to aHUS (AD)

CD46 (MCP)

Membrane cofactor protein isoform 1 precursor

120920

Approximately 12% of aHUS

AD, AR

Susceptibility to aHUS 2

CFB

Complement factor B preproprotein

138470

Rare

AD

Complement factor B deficiency, susceptibility to aHUS 4

CFD

Complement factor D isoform 1 preproprotein

134350

Rare

AR

Complement factor D deficiency

CFH

Complement factor H isoform a precursor

134370

Approximately 30% of aHUS patients

AD, AR

Complement factor H deficiency, susceptibility to aHUS 1

CFHR1

Complement factor H-related protein 1 precursor

134371

Rare

AD, AR

Susceptibility to aHUS

CFHR3

Complement factor H-related protein 3 isoform 1 precursor

605336

Rare

AD, AR

Susceptibility to aHUS

CFHR5

Complement factor H-related protein 5 precursor

608593

3% of aHUS

AD

Nephropathy due to CFHR5 deficiency

CFI

Complement factor I isoform 2 preproprotein

217030

4%-10% of aHUS

AD, AR

Complement factor I deficiency (AR), susceptibility to aHUS (AD)

DGKE

Diacylglycerol kinase epsilon

601440

Rare

AR

Nephrotic syndrome Type 7, susceptibility to aHUS

PLG

Plasminogen isoform 1 precursor

173350

Rare

AR

Dysplasminogenemia, plasminogen deficiency Type I

THBD

Thrombomodulin precursor

188040

Approximately 3%-5% of aHUS

AD

Thrombophilia due to thrombomodulin defect, susceptibility to aHUS

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

 

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Clinical Correlations:

Some individuals who have involvement of one or more of the genes on the panel may have a variant that is not identified by the methods performed (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of disease. Test results should be interpreted in context of clinical findings, family history, and other laboratory data (especially complement serological analyses). Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

Note, several genes included on this panel (C3, CFB, CFH, CFHR1, CFHR3, and CFI) have high frequency (>1%) sequence variants or haplotypes that have been identified as protective alleles or susceptibility alleles for age-related macular degeneration (ARMD). High frequency variants in these genes (>1%) are not included on this report.

 

For predictive testing of asymptomatic individuals, it is often useful to first test an affected family member. Identification of a pathogenic variant in an affected individual allows for more informative testing of at-risk individuals.

 

Technical Limitations:

Next-generation sequencing may not detect all types of genetic variants. The variant detection software has lower detection efficiency for insertion/deletion variants as compared to single nucleotide variants. Therefore, small deletions and insertions greater than 8 nucleotides in length may not be detected by this test. Copy number variations (CNV) are not currently reported for any of the genes on this panel. Additionally, rare polymorphisms may be present that could lead to false-negative or false-positive results. In some cases, DNA variants of undetermined significance may be identified. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion/duplication analysis. If the patient has had an allogeneic blood or bone marrow transplant or a recent (ie, <6 weeks from time of sample collection) heterologous blood transfusion, results may be inaccurate due to the presence of donor DNA. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

 

Reclassification of Variants Policy:

At this time, it is not standard practice for the laboratory to systematically review likely deleterious alterations or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time. Consultation with a healthcare provider, or team of healthcare providers, with expertise in genetics and primary immunodeficiencies, is recommended for interpretation of this result.

 

A list of benign and likely benign variants detected for this patient is available from the lab upon request.

 

Contact the laboratory if additional information is required regarding the transcript or human genome assembly used for the analysis of this patient's results.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Picard C, Gaspar HB, Al-Herz W, et al: International Union of Immunological Societies: 2017 Primary Immunodeficiency Disease Committee Report on Inborn Errors of Immunity, J Clin Immunol 2018;38:96-128

2. Noris M, Bresin E, Mele C, et al: Genetic Atypical Hemolytic-Uremic Syndrome. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle, 1993-2018. 2007 Nov 16 (Updated 2016 June 9). Accessed July 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1367/

3. Kavanagh D, Goodship THJ: Atypical hemolytic uremic syndrome, genetic basis and clinical manifestations. Hematology (ASH) 2011;15-20

4. George JN, Nester CM: Syndromes of thrombotic microangiopathy. N Engl J Med 2014;371:1654-1666

5. Go RS, Winters JL, Leung N, et al: Thrombotic Microangiopathy Care Pathway: A Consensus Statement for the Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group. Mayo Clin Proceedings 2016;91(9):1189-1211

Special Instructions Library of PDFs including pertinent information and forms related to the test