SP058GENETIC ASPECTS OF OBSTETRIC AHUS

Abstract

INTRODUCTION AND AIMS: Atypical haemolytic uremic syndrome (aHUS) is a systemic disease featuring uncontrolled activation of the alternative complement pathway due to either a genetic defect of the complement system or an autoimmune pathology (antibodies against factor). According to the modern concept of aHUS, a genetic defect in the complement system only predisposes to the development of aHUS. For realization of genetic predisposition the additional activation of the complement system is required, such as pregnancy (7% in the structure of aHUS causes). The aim of our study was to examine the features of obstetric aHUS in relation to genetics. METHODS: The study included 5 women between 20 to 33 years old (28,2 ± 4,8 years) with obstetric aHUS. Prior to the development of acute obstetric situation all 5 patients (pts) were healthy. After aHUS diagnosis, all pts received complement blocking treatment with eculizumab. Human exome sequencing and analysis was performed by Genotek Inc. Whole blood DNA was subjected to solution capture (SureSelect, Agilent Technologies) and the resulting libraries were subsequently sequenced by synthesis on Illumina HiSeq2000 system employing paired end reads (100 bp×2). The Human Gene Mutation Database was used for annotation of known pathogenic variants and variants that are synonymous /non-synonymous to them. Variants pathogenicity was predicted according to guidelines for the interpretation of sequence variants provided by American College of Medical Genetics and Genomics. RESULTS: All pts developed aHUS after delivery. At the same time the development of aHUS in all cases was preceded by a various complement-activating conditions(Tab 1). All of these pregnancies ended in live births, and 4 out of 5 on the birth weight matched gestational age and did not have signs of malnutrition. All pts had complete TMA: decreased Hb level (mean 55,4 g /l), thrombocytopenia (mean 34,2 109/mkl) and marked increase in LDH level (mean 4546,6 U/L). Renal involvement in all cases was presented with AKI (mean serum creatinine 539,2 umol/l), oliguria or anuria that required initiation of hemodialysis. All patients had extrarenal manifestations of TMA with involvement of liver, lungs and CNS. The genetic profile of patients. Mutations (LP-likely pathogenic) associated with the development of aHUS were found only in 2 cases (Tab. 1). Two pts are carriers of identical high-risk mutations. Variants of complement system genes with unknown clinical significance (US) have been identified in all women. Moreover, we found the same combination of different gene variants in our patients (Tab. 1). CONCLUSIONS: We believe that extra complement-activating conditions noted in all our cases “overload” the complement regulation mechanisms in pts with genetic predisposition. Possibly similar combination of gene variants can be regarded as a predisposing factor for the development of aHUS. Consequently, there is an excessive activation of the complement system with the development of “complementary storm” postpartum and clinical manifestation on aHUS. (Table Presented).