MAC Plus Study: A Retrospective Study Correlating DNA Variants, Clinical Course and Outcomes from 187 Patients Who Underwent Testing Using an Atypical Hemolytic Uremic Syndrome and Thrombotic Microangiopathy Genetic Sequencing Panel

Atypical hemolytic uremic syndrome (aHUS) is a rare, potentially fatal disease that is often difficult to diagnose. The clinical presentation and pathogenesis of aHUS can overlap with several other rare, serious diseases (e.g., inherited thrombotic thrombocytopenia (TTP), shiga-toxin hemolytic uremic syndrome (STEC-HUS), and C3 glomerulopathy (C3G)). In many cases, a positive genetic finding can help clarify the diagnosis, guide treatment decisions, and inform prognosis.

We have sequenced >2000 patients with a genetic panel targeting a collection of rare thrombotic microangiopathy (TMA) diseases and here we report the clinical course and outcomes for a subset (n=187). We cataloged all of the rare variants detected from sequencing ADAMTS13, C2, C3, C3AR1, CD46 (MCP), CFB, CFD, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, DGKE, MASP2, MMACHC, THBD, PLG, WT1 and the variant in C5 causing eculizumab resistance (p.Arg885). We collected data including clinical lab values, potential triggers, diagnoses, treatments, and outcomes. Our cohort here is distinct in that it is not a collection of patients clinically diagnosed with a specific disease (e.g., aHUS); instead, this cohort comprises real-world cases where the physicians sought out genetic testing for their patients as a part of the diagnostic picture. Physicians may be especially likely to seek out genetics when the diagnosis is especially murky. Patients treated with eculizumab responded well (52 responded, 7 did not respond, 8 unknown). Among patients who initiated eculizumab therapy, 34/67 discontinued its use and zero reported disease relapse. Of the 34 discontinuing eculizumab, 8 had a non-aHUS, non-TMA diagnosis while the 33 patients continuing therapy had only 1 with a non-aHUS, non-TMA diagnosis. In this cohort, 38% (71/187) ended up with a diagnosis of aHUS, 14% (27/187) were diagnosed with C3G/C3G-TMA, and 21% (40/187) were diagnosed with some other form of thrombotic microangiopathy (e.g., hypertension-TMA). Only 19 patients had a clear-cut positive genetic finding with 13 of those being the large, homozygous deletion of CFHR1 that is associated with CFH autoantibodies. 52 cases were negative for genetics while 86 had one or more rare variants of unknown significance. The difficulty in interpreting rare variants in the context of very rare, partially penetrant diseases like aHUS underscores the need for more genetic and clinical data to be made publicly available. The collection of data here will be a valuable resource for clinicians and scientists actively conducting research on these rare diseases and perhaps even more valuable for the clinical scientists and genetic counselors seeking context and comparisons for their own patients' variants, where the biggest problem currently is that most rare variants for these diseases are unfortunately variants of unknown significance.

Moon:Machaon Diagnostics, Inc.: Current Employment. Kain:Machaon Diagnostics, Inc.: Current Employment. Fervenza:Alexion Pharmaceuticals: Consultancy. Erickson:Mayo Clinic: Consultancy, Current Employment, Membership on an entity's Board of Directors or advisory committees. Hanna:Roche: Research Funding; Alexion Pharmaceuticals: Research Funding, Speakers Bureau; GSK: Speakers Bureau; Otsuka Pharmaceutical: Other: NephU; Aurinia Pharmaceuticals: Speakers Bureau; Apellis Pharmaceuticals: Research Funding. Brakeman:Alnylam Pharmaceuticals: Consultancy. Dvorak:Alexion Pharmaceuticals: Consultancy; Omeros Corporation: Consultancy. Lim:Machaon Diagnostics, Inc.: Current Employment. Venkataramani:Machaon Diagnostics, Inc.: Current Employment. Ero:Machaon Diagnostics, Inc.: Current Employment. Lewis:Machaon Diagnostics, Inc.: Current Employment; Alexion Pharmaceuticals: Honoraria, Speakers Bureau.