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Genetic Analysis of 400 Patients Refines Understanding And BASIC RESEARCH www.jasn.org Genetic Analysis of 400 Patients Refines Understanding and Implicates a New Gene in Atypical Hemolytic Uremic Syndrome Fengxiao Bu,1,2 Yuzhou Zhang,2 Kai Wang,3 Nicolo Ghiringhelli Borsa,2 Michael B. Jones,2 Amanda O. Taylor,2 Erika Takanami,2 Nicole C. Meyer,2 Kathy Frees,2 Christie P. Thomas,4 Carla Nester,2,4,5 and Richard J.H. Smith2,4,5 1Medical Genetics Center, Southwest Hospital, Chongqing, China; and 2Molecular Otolaryngology and Renal Research Laboratories, 3College of Public Health, 4Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, and 5Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa ABSTRACT Background Genetic variation in complement genes is a predisposing factor for atypical hemolytic uremic syndrome (aHUS), a life-threatening thrombotic microangiopathy, however interpreting the effects of genetic variants is challenging and often ambiguous. Methods We analyzed 93 complement and coagulation genes in 400 patients with aHUS, using as controls 600 healthy individuals from Iowa and 63,345 non-Finnish European individuals from the Genome Aggre- gation Database. After adjusting for population stratification, we then applied the Fisher exact, modified Poisson exact, and optimal unified sequence kernel association tests to assess gene-based variant burden. We also applied a sliding-window analysis to define the frequency range over which variant burden was significant. Results We found that patients with aHUS are enriched for ultrarare coding variants in the CFH, C3, CD46, CFI, DGKE,andVTN genes. The majority of the significance is contributed by variants with a minor allele frequency of ,0.1%. Disease-related variants tend to occur in specific complement protein domains of FH, CD46, and C3. We observed no enrichment for multiple rare coding variants in gene-gene combinations. Conclusions In known aHUS-associated genes, variants with a minor allele frequency .0.1% should not be considered pathogenic unless valid enrichment and/or functional evidence are available. VTN,which encodes vitronectin, an inhibitor of the terminal complement pathway, is implicated as a novel aHUS- associated gene. Patients with aHUS are not enriched for multiple rare variants in complement genes. In aggregate, these data may help in directing clinical management of aHUS. J Am Soc Nephrol 29: 2809–2819, 2018. doi: https://doi.org/10.1681/ASN.2018070759 Atypical hemolytic uremic syndrome (aHUS) complement-mediated disease, aHUS develops in defines a spectrum of thrombotic microangiopa- people carrying predisposing genetic abnormalities thies (TMAs) characterized by hemolytic anemia, thrombocytopenia, and acute renal injury not Received July 25, 2018. Accepted September 12, 2018. Escherichia coli caused by Shiga toxin-producing Published online ahead of print. Publication date available at 1,2 or ADAMTS13 deficiency. It is ultrarare, with www.jasn.org. an incidence of approximately 0.5 per million per Correspondence: Dr. Richard J.H. Smith, Molecular Otolaryn- year and until the introduction of eculizumab, a gology and Renal Research Laboratories, University of Iowa, 285 humanized mAb against C5 that blocks the termi- Newton Road, 5270 CBRB, Iowa City, IA 52242. Email: richard- nal pathway of the complement cascade, it carried a [email protected] very poor prognosis.3,4 As the quintessential Copyright © 2018 by the American Society of Nephrology J Am Soc Nephrol 29: 2809–2819, 2018 ISSN : 1046-6673/2912-2809 2809 BASIC RESEARCH www.jasn.org in complement genes after exposure to a host of triggering/ Significance Statement causal events that include infection, drugs, malignancy, trans- plantation, and pregnancy.2 Although atypical hemolytic uremic syndrome (aHUS) is caused by Genetic studies in patients with a clinical diagnosis of complement dysregulation, in half of patients, mutations are not fi aHUS identify mutations in alternative pathway-related genes identi ed in complement genes. The authors screened 400 patients with aHUS for variation in 93 complement and coagulation genes, 5–9 in up to half of cases. The list of extensively reported aHUS finding that patients with aHUS are more likely than controls to carry genes includes CFH (implicated in approximately 25% of rare coding variants in CFH, C3, CD46, CFI,andDGKE, but not in patients), CD46 (approximately 10%), C3 (approximately CFB, PLG, and THBD. They also demonstrate VTN (a gene not 6%), CFI (approximately 6%), CFB (approximately 2%), previously identified as aHUS-related) as enriched in patients, and fi THBD (approximately 2%), and a noncomplement exception, highlight speci c protein domains in CFH, C3, and CD46 as aHUS- related. They propose a minor allele frequency threshold of 0.1% DGKE 2 (approximately 3%). Autoantibodies against factor H for a variant to be considered as possibly disease relevant. These (FHAA) account for 5%–13% of cases and are associated with data may help in directing clinical management of patients with the absence of both copies of CFHR1.10 If a genetic variation is aHUS. found, it is often considered a predisposing factor rather than a direct cause of aHUS. This distinction reflects the landscape of aHUS is changing and other complement genes like high variability in disease penetrance, with the notable excep- C4BPA,19 C7,20 and CFHR2,21 and noncomplement genes like tion being pathogenic variants in DGKE, which follow an au- CBL, INF2,22–24 MMACHC,25–27 CLU,28 PLG,29 and F12,30 have tosomal recessive inheritance pattern.11–14 been implicated in pathogenesis, we sought to analyze rare cod- The term “primary aHUS” has been proposed by some cli- ing variant burden in a large aHUS cohort in which we control nicians to designate patients with aHUS who carry a genetic for population stratification, integrate two control cohorts, and abnormality in complement genes; however, the distinction be- study a large number of genes. tween primary and secondary aHUS is challenging for several reasons. First, significant complement variants are not identified in a large portion of the patients with aHUS who respond to METHODS terminal complement-blocking treatment.3 Second, in many persons who carry genetic variants in complement genes, the Participants disease does not develop in the absence of triggering events. Patients referred to the Molecular Otolaryngology and Renal Third, aHUS shows variable penetrance, making it difficult to Research Laboratories at the University of Iowa (UI) for a ge- interpret the role many genetic variants play in disease. Fourth, netic evaluation for TMAs were enrolled in this study. Atypical crosstalk between the complement and coagulation pathways HUS was diagnosed by the referring physicians on the basis of makes it challenging to provide an integrated interpretation of the presence of hemolytic anemia, thrombocytopenia, and re- genetic results. Lastly, a TMA lesion is a component of many nal injury, absence of Shiga toxin-producing E. coli,and diseases, which confounds the diagnosis of aHUS.1,2,5 ADAMTS13 activity .10%. Patients were screened for vari- When genetic variants are identified in a patient with aHUS, ants in 93 TMA-related genes (Supplemental Table 1) using a it is critically important to determine their clinical significance, targeted genomic enrichment panel known as CasCADE/ as it has a bearing on long-term anticomplement therapy. Pur- GRP.29,31 The UI control group comprised 600 unrelated Eu- ported disease variants are often defined as such because they ropean Americans (300 males and 300 females) screened by are not detected in a few hundred healthy controls. This ap- the SeqCap EZ whole-exome panel plus custom targeted re- proach has been challenged by publications showing that ul- gions (v1/v2; Roche Sequencing, Pleasanton, CA).32 Both ca- trarare but benign variants are not uncommon.15 For example, ses and UI controls are genetically of European descent, with Marinozzi et al.16 demonstrated experimentally that nine out other ethnicities removed to decrease population stratification of 15 reported CFB gene mutations were unrelated to aHUS (Supplemental Figures 2 and 3). Relatedness analysis was done pathogenesis. Novel variants have also been identified in CFH to eliminate close relatives. A second control cohort of 63,345 that may be unrelated to aHUS.17 Although these reports sup- individuals was accessed by utilizing the non-Finnish Euro- port the value of functional studies to assess variant impact, pean (NFE) population extracted from the Genome Aggrega- these studies are labor intensive and difficult, making func- tion Database (gnomAD).15 The study was approved by the tional assessment impractical in every instance. Institutional Review Board of Carver College of Medicine at Phenotypic variability in presentation adds another layer of UI (IRB ID# 201502804). complexity. A recent collaborative, multi-institution study failed to find enrichment for rare genetic variants in the CFB, THBD, Sequencing and Bioinformatics and PLG genes in patients with aHUS compared with controls Genomic DNA was extracted from whole blood using the Gentra from the Exome Aggregation Consortium database.18 That Puregene Kit (QIAGEN, Valencia, CA) or Chemagic 360 instru- study, however, did not control for population stratification, ment (PerkinElmer Inc., Waltham, MA). Targetedgenomic enrich- which affects rare variant burden (Supplemental Figure 1). In ment was automated using the customized SureSelect Target addition, only a few genes were considered. Because
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