Atypical hemolytic uremic syndrome (aHUS) [17 genes]

Atypical hemolytic uremic syndrome (aHUS) is a disease characterized by a triad of manifestations: microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. aHUS is a consequence of the alteration in the regulation of the activation of the complement system on cell surfaces, leading to endothelial damage mediated by C5 and the terminal complement pathway. This alteration can be caused by monogenic genetic alterations, risk haplotypes, external and internal triggers such as chronic infections, specific long-term pharmacological treatments, autoimmune diseases, pregnancy, and surgical interventions, among other factors. Therefore, events that activate complement lead to continuous and unrestricted complement activity, producing widespread endothelial injury. Pathogenic mutations include those that result in loss of function in a complement regulatory gene (CFH, CFI, CD46 or THBD) or gain of function in an effector gene (CFB or C3), as well as pathogenic variants in more than two genes related to the same pathway. In addition to genes affecting complement pathways, differential diagnoses of diseases with overlapping phenotypes should also be included.

1-9/100,000

The genetic diagnosis of aHUS provides precise identification of the cause of the disease, which is a definitive diagnostic criterion. Identification of the molecular cause provides necessary information for genetic counseling and patient management. The treatment of aHUS mediated by complement activation is based on the use of anti-C5 monoclonal antibodies. The prognosis and penetrance of the disease vary depending on the genetic defect carried by the patient, so a positive genetic study provides relevant predictive data.

The aHUS genetic diagnosis panel is indicated when there is suspicion of the disease, characterized by the triad microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure and presentation of at least one of the following criteria:

  • One or more family members diagnosed with aHUS.
  • Individuals with HUS recurrence.
  • Exposure to triggers, excluding Shiga toxin.

It is estimated that approximately 60% of patients diagnosed with aHUS carry a genetic defect in the genes associated with the disease.

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Atypical hemolytic uremic syndrome (aHUS)

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Technique: NGS capture panel

Turnaround time (TAT): 25 days

Ref. S-202008468

Atypical hemolytic uremic syndrome (aHUS): View panel

The aHUS genetic diagnosis service includes genes from the alternative pathway of the complement system and aHUS phenocopies that include genes other than those of the complement system. Within these genes, highly penetrant variants that cause monogenic aHUS and risk haplotypes that intervene as modifiers of the disease are studied. Risk haplotypes include the following haplotypes:

  • CFH gene: H1, H2, H3 haplotype.
  • CFHR3/CFHR1 genes: *A, *B, H4 haplotypes.
  • CD46 gene: MCP1, MCP2, MCP3 haplotypes.
  • C3 gene: Risk polymorphisms.
  • THBF gene: Risk polymorphism.

  • ADAMTS13
  • C3
  • CD46
  • CFB
  • CFH
  • CFHR1
  • CFHR2
  • CFHR3
  • CFHR4
  • CFHR5
  • CFI
  • CFP
  • DGKE
  • G6PD
  • MMACHC
  • THBD
  • VTN

Priority Genes : Genes where there is sufficient evidence (clinical and functional) to consider them associated with the disease; they are included in the clinical practice guidelines.
Secondary Genes: Genes related to the disease, but with a lower level of evidence or that constitute sporadic cases.
* Candidate Genes: Not enough evidence in humans, but potentially associated with the disease.

References

  1. Sansbury FH, Cordell HJ, Bingham C, Bromilow G, Nicholls A, Powell R, Shields B, Smyth L, Warwicker P, Strain L, Wilson V, Goodship JA, Goodship TH, Turnpenny PD. Factors determining penetrance in familial atypical haemolytic uraemic syndrome. J Med Genet. 2014 Nov;51(11):756-64. doi: 10.1136/jmedgenet-2014-102498. Epub 2014 Sep 26. PubMed PMID: 25261570.
  2. Goicoechea de Jorge E, López Lera A, Bayarri-Olmos R, Yebenes H, Lopez-Trascasa M, Rodríguez de Córdoba S. Common and rare genetic variants of complement components in human disease. Mol Immunol. 2018 Oct;102:42-57. doi: 10.1016/j.molimm.2018.06.011. Epub 2018 Jun 18. Review. PubMed PMID: 29914697.
  3. Noris M, Bresin E, Mele C, Remuzzi G. Genetic Atypical Hemolytic-Uremic Syndrome. 2007 Nov 16 [updated 2016 Jun 9]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. PubMed PMID: 20301541.