Atypical hemolytic uremic syndrome (aHUS) is a rare renal disease (two per one million in the USA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Both sporadic (80% of cases) and familial (20% of cases) forms are recognized. The study of familial aHUS has implicated genetic variation in multiple genes in the complement system in disease pathogenesis, helping to define the mechanism whereby complement dysregulation at the cell surface level leads to both sporadic and familial disease. This understanding has culminated in the use of Eculizumab as first-line therapy in disease treatment, significantly changing the care and prognosis of affected patients. However, even with this bright outlook, major challenges remain to understand the complexity of aHUS at the genetic level. It is possible that a more detailed picture of aHUS can be translated to an improved understanding of disease penetrance, which is highly variable, and response to therapy, both in the short and long terms. 1. Introduction Hemolytic uremic syndrome (HUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. It is most frequently caused by infections of Shiga-like toxin producing bacteria, such as Escherichia coli strain O157？:？H7, O111？:？H8, O103？:？H2, O123, and O26 [1]. In approximately 10% of HUS cases, there is no association with Shiga-like toxin. These cases are classified as atypical HUS (aHUS) and occur with an incidence of about 2 per million in the USA [1, 2]. aHUS patients have a poorer prognosis than those with typical HUS, with acute phase aHUS mortality of about 8% [3, 4], and with 50%–80% of aHUS patients progressing to end-stage renal failure [1]. However, it is important to note that epidemiological outcomes data are relatively out of date because of the development of better diagnostic, treatment, and management strategies. Atypical HUS can be classified as sporadic or familial. Familial aHUS is defined as the presence of aHUS in at least two members of the same family with diagnoses at least 6 months apart [1, 3, 5]. It accounts for less than 20% of aHUS cases [3]. In familial aHUS (and also sporadic aHUS), genetic (e.g., gene mutations, rare variants, and risk haplotypes) and acquired abnormalities (e.g., autoantibodies against factor H) are found in ~70% of patients [6]. Gene mutations are usually found in complement genes, such as factor H (CFH), factor I (CFI), factor B (CFB), complement component 3 (C3), and membrane cofactor protein (MCP or CD46). Evidence
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