Observations from the First 1,000 Suspected aHUS Patients, Tested By a Rapid aHUS Genetic (NGS) Panel: Causative Genes Identified in a Subpopulation of Our Database

Atypical Hemolytic Uremic Syndrome (aHUS) is a life-threatening, progressive genetic disease. aHUS results from uncontrolled activation of the complement system, which then targets endothelial cells, leading to thrombotic microangiopathy (TMA). The disease commonly progresses to kidney failure and death. Currently, aHUS is diagnosed by ruling out other diseases which cause TMA. Treatment is often performed with eculizumab, a terminal inhibitor of complement, which is expensive. Due to the severity of aHUS and the expense of treatment, rapid diagnosis of the disease is desirable. With a genetic sequencing assay for aHUS with a turnaround time of two days, we have gained comprehensive genetic understanding of a population of patients displaying acute clinical presentation of aHUS. The genes sequenced for the assay are CFH, MCP (CD46), CFI, C3, CFB, CFHR1, CFHR3, CFHR4, CFHR5, THBD, PLG, and DGKE, alongside deletion/duplication analysis for CFHR1-3 and CFHR1-4. Currently, over 1000 patients have been tested using this panel. We reviewed de-identified aggregate results for a subset of patients tested using this panel (416 patients). We tabulated the frequency of clear-cut causative genetic variants in each of the genes among the patients tested positive for aHUS. The most common variant among the positives tabulated is the large deletion in CFHR1, at 23%. 23% of positives have a variant in MCP, 15% in CFH, 10% in THBD, 9% in CFI, 6% in C3, 6% in PLG, 5% in CFB, 3% in CFHR5, and 1% in DGKE. Furthermore, we report the frequency of positive, equivocal and negative results, breakdown of rare variant types per gene, frequency of patients with multiple rare variants, frequency of novel variants in the genes sequenced, frequency of deletion-duplication events in CFHR1-3 and CFHR1-4, and the CFH and MCP/CD46 risk polymorphisms. These data may provide the largest overview to date of genetic variants in risk-factor genes in patients where an aHUS diagnosis is suspected.