Comprehensive Complement Analysis of atypical Hemolytic Uremic Syndrome in Argentina: a case study

CÉLIA DOS SANTOS; SARAH ROBERTS; MARÍA FABIANA ALBERTO; ANALÍA SÁNCHEZ-LUCEROS; NICOLO GHIRINGHELLI BORSA; RENEE GOODFELLOW; YUZHOU ZHANG; RICHARD J.H. SMITH; AMANDA TAYLOR; MICHAEL JONES; EMILY ANDERSON; GUSTAVO GRELONI

Madrid

Congreso; 17th European Meeting on Complement in Human Disease; 2019

European Complement Network

Atypical Hemolytic Uremic Syndrome (aHUS) is characterizedby thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury(AKI). Because the disease is often associated with genetic or acquired driversof the complement system?s alternative pathway, comprehensive genetic andbiomarker testing facilitates an accurate diagnosis and appropriate treatment.We report a case of an Argentinean 27-year-old female presenting withpost-partum aHUS; she has five unaffected first-degree relatives. Targetedgenomic enrichment with massive parallel sequencing (TGE+MPS) was performed toscreen 11 genes associated with complement-mediated diseases and multiplexligation-dependent probe amplification (MLPA) analyzed copy-number variations(CNVs) in the CFH-CFHR5 genomicregion. To assess genetic variants identified in the family, biomarker andfunctional testing were measured by ELISA (including allele specific ELISA),radial immunodiffusion (RID) and C3 deposition assay. TGE+MPS identified onenovel CFH variant (p.Cys192Tyr), anovel CFI variant (p.Val397Leu) andan ultra-rare variant in the THBDgene (p.Pro263Ala). MLPA revealed normal copy-number in the CFH-CFHR5 genomic region. Follow-upallele specific ELISA tested in the patient?s mother (p.H402Y heterozygote)revealed that the p.Y402 CFH allelewas a null allele resulting in low FH serum level. Borderline low FI levelswere also confirmed in all individuals carrying the CFI variant, consistent with a hypomorphic allele and a likelypathogenic classification. Extensive functional assays of the proband?scomplement biomarker profile identified several abnormal levels indicatingongoing complement dysregulation. This case highlights the importance ofgenetic testing and complement biomarker analysis to provide an accuratediagnosis in patients presenting with aHUS.