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aHUS Genetic Panel 3.0

Justification

The clinical presentation of thrombotic microangiopathy (TMA) has been associated with multiple genetic disease including atypical hemolytic uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP), C3 glomerulopathy (C3G, comprising dense deposit disease and C3 glomerulonephritis), congenital B12 deficiency and others. These are difficult-to-diagnose, very sick patients with distinct treatment depending on the nature of the TMA. Accurate, rapid diagnosis is critical. Additionally, patients with the C5 p.Arg885 polymorphism may respond poorly to the current approved therapy, eculizumab. Note: this is the third time (3.0 name designation) we have updated the gene list to reflect the most current understanding of aHUS/TMA in the scientific literature.

STAT: < 48 hours (M-F)

NGS

Draw Tube: Purple Top

Sample Type: EDTA Whole Blood

DRAW KITS AVAILABLE

Specimen Requirements

Sample Type Volume Required Minimum Volume Stability
PREFERRED EDTA Whole Blood 3mL 1mL Room Temp.: 1 month
Refrigerated: 1 month
ALTERNATIVE Cheek swab 2 swab - Room Temp.: 1 month
Refrigerated: 1 month
REJECTION CRITERIA Sample contamination; sample compromised
SPECIAL INSTRUCTIONS Post bone marrow transplant (post-BMT) patients require a cheek swab sample to test the transplant recipient; post-BMT patients require a venous blood sample to test the bone marrow donor.

General Information

METHODOLOGY NGS
STAT TAT < 48 hours (M-F)
STAT TAT Performance > 90% of results released in 48 hours
ROUTINE TAT < 5 days (M-F)
ALTERNATIVE NAMES TMA genetic panel; TMA-Complete; complement-mediated TMA panel; C3 glomerulopathy panel; complement-mediated HUS; cm-HUS; aHUS
DESCRIPTION 22 genes associated with TMAs have been sequenced and analyzed as part of this panel: ADAMTS13, C2, C3, C3AR1, C4BPA, C4BPB, CD46 (MCP), CFB, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, DGKE, INF2, MMACHC, PLG, THBD, VTN and WT1, plus the region of C5 underlying poor response to eculizumab and a specific, gain-of-function intronic variant (c.914-5T>A) in TSEN2 linked to aHUS. In addition to picking up both known and novel single nucleotide variants, this test also detects the large deletions in CFHR3-1 and CFHR1-4. Rare, pathogenic CFH fusions are best detected using our CFH MLPA assay. Sanger sequencing is performed to confirm certain variants.
LIMITATIONS This test will not detect variants located outside of the targeted DNA regions. This test is not optimized to detect chimerism or somatic mosaicism. This test will detect small indels but may miss larger deletions or duplications. Balanced structural variants will not be detected unless specifically targeted by a custom PCR assay.
NORMAL RANGE Interpretation: Negative
ASSOCIATED TESTING Soluble Complement 5b-9 (sC5b-9), CFH Region Deletion/Duplication Analysis by MLPA, Anti-CFH Antibody, ADAMTS13 Activity
REFERENCES

Bu, F et al. Clin Dev Immunol 2012; 2012: 370426
Lemaire, M et al. Nature Genetics 2013; 45:531
Noris M, Caprioli J, Bresin E, et al. Clin J Am Soc Nephrol 2010; 5:1844.
Osborne (2018) J Immunol 200, 7;
Levy (2001) Nature 413;
Beck (2017) Pediatr Nephrol 32, 5;
Alge (2017) BMC Nephrol 18, 1;
Bu (2014) J Am Soc Nephrol 25, 1;
Xiao (2016) Mol Immunol 77;
Nishimura (2014) New Engl J Med 370, 7.
SAMPLE REPORT Upon request
NEW YORK STATE APPROVED Yes

Test Codes

ORDER CODE P3346
CPT CODE 81404, 81405, 81479
LOINC CODE 99967-2