Identification of two novel single nucleotide variants of the complement Factor H (CFH) and Factor I (CFI) genes in a familial form of atypical hemolytic uremic syndrome (aHUS)

CÉLIA DOS SANTOS; RICHARD J H SMITH; ANA C KEMPFER; MARÍA M CASINELLI; GUSTAVO GRELONI; ANALÍA SÁNCHEZ-LUCEROS

Montpellier

Congreso; 62nd Annual Meeting of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis; 2016

Background: Atypical hemolytic uremic syndrome(aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopeniaand acute renal failure. Most aHUS cases involve sequence variations in genesencoding complement proteins.Aims: A 27-year-old woman with an episode ofthrombotic microangiopathy 1 month post-partum presented with severe anemia(hematocrit: 22%, hemoglobin: 7.6 g/dL), thrombocytopenia (138 000/μL), elevatedLDH (654 IU/L) and deteriorating renal function (creatinine: 3.3 mg/dL); sheand her available relatives were screened for mutations/polymorphisms inaHUS-associated complement genes.Methods: After extracting gDNA from whole blood(Wizard® Genomic DNA Purification Kit, Promega), PCR products of coding sequencesand intronic flanking regions of complement genes were sequenced by ABI PRISM310 Genetic Analyzer (Applied Biosystems). Insilico analysis for pathogenicity was completed with Polyphen2-HDIV, PhyloP/Phastcons(MutationTaster), SIFT and PANTHER. All the participants provided informed written consent.Results: The patient was diagnosed with aHUS (allADAMTS13 parameters were normal).  Comprehensive screening of aHUS-associatedcomplement genes identified two novel single nucleotide variants: CFH c.575G>A, p.C192Y (exon 5)(NM_000186), predicted to be pathogenic by 4 of 5 available pathogenicityprediction programs; and CFI c.1189G>T,p.V397L (exon 11) (NM_000204), predicted pathogenic by 0 of 6 availablepathogenicity prediction programs. Figure 1 shows the segregation of thesevariants in the pedigree. Conclusion:  We identified two novel genetic variants in theCFH and CFI genes in a patient with aHUS, who inherited one variant fromeach parent. Although the CFI variantis predicted to be benign, the CFHvariant is predicted to be damaging. It is located in exon 5, which encodes aportion of the factor H protein implicated in binding to C3b.