Complement Abnormalities in a Cohort of Argentinean Patients with Atypical Hemolytic Uremic Syndrome

CÉLIA DOS SANTOS; NICOLO GHIRINGHELLI BORSA; AMANDA TAYLOR; MICHAEL JONES; NATALIA MOGOLLÓN MOLINA; MARÍA F ALBERTO; RITA MARCELA FORTUNATO; MARTA ADRAGNA; GUSTAVO GRELONI; YUZHOU ZHANG; RICHARD J.H. SMITH; ANALÍA SÁNCHEZ-LUCEROS

Congreso; XXVII Congress of the International Society on Thrombosis and Haemostasis; 2019

Atypical Hemolytic Uremic Syndrome (aHUS) is an ultra-rare thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and renal failure that is associated with dysregulation of the alternative complement pathway. Its diagnosis is challenging for physicians and is facilitated by genetic and serologic studies of the complement system, which also help to predict disease outcome and guide treatment. Aim: To describe the global framework of aHUS in an Argentinean patient cohort. Targeted genomic enrichment with massive parallel sequencing was used to screen 11 genes implicated in complement-mediated TMA in a cohort of 35 probands presenting with aHUS (71% were female and 26% of the total population was under 18 years-old). Concurrently, multiplex ligation-dependent probe amplification (MLPA) was used to study copy-number variations (CNVs) in the CFH-CFHRs (Complement Factor H-Complement Factor H related) genomic region. Complement biomarkers were measured by ELISA and radial immunodiffusion (RID) on patients with significant genetic findings. All participants of this study gave their informed consent and the study was approved by the institutional ethical committee.Targeted genomic enrichment with massive parallel sequencing and MLPA were completed on 31 and 34 of 35 patients, respectively. In 13 patients, 15 heterozygous variants and 2 CNVs were found. Eight patients carried a single variant, three carried combined variants, and two carried CFH-CFHRs CNVs (Table 1). Six variants were classified as pathogenic, seven as uncertain significance and two as likely benign. The investigation of complement protein levels assisted in the classification of genetic variants. Functional studies also identified one patient positive for factor H autoantibodies (FHAA). Genotype-phenotype correlations were confirmed on samples collected in the acute phase. In this study of Argentinean aHUS patients (the first to be performed) we show that 41% of cases were associated with complement abnormalities.