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Variants in complement genes are uncommon in patients with anti-factor H autoantibody-associated atypical hemolytic uremic syndrome

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Abstract

Background

Coexisting genetic variants in patients with anti-factor H (FH)-associated atypical hemolytic uremic syndrome (aHUS) have implications for therapy. We estimated the prevalence of complement genetic variants in children with anti-FH aHUS from a prospective nationwide cohort and determined if significant genetic variants impact long-term kidney outcomes.

Methods

Of 436 patients in the database, 77 consecutive patients, 21 with a relapse and 9 with kidney failure and/or death were included. Targeted sequencing, using a 27-gene panel including CFH, CFI, CFB, C3, CD46, PLG, DGKE, and THBD and multiplex ligation-dependent probe amplification of CFH-CFHR region, was performed. The adverse outcome was eGFR < 30 ml/min/1.73 m2 or death.

Results

Patients had high anti-FH titers 5670 (2177–13,545) AU/ml, relapsing course (42.1%), and adverse outcomes (19.6%). Variants, chiefly of unknown significance, were found in 7 (6.5%; 95% CI 3.1–13.2%); a pathogenic variant was found in one patient. Homozygous deletion of CFHR1 was present in 91.6% compared to 9.8% in 184 healthy controls. Plasma exchanges and immunosuppression showed a trend of improving outcomes, independent of genetic defects (HR 0.32; P = 0.070). Meta-analysis of 18 studies (384 patients) showed that the pooled prevalence of pathogenic and likely pathogenic variants was 3% (95% CI 0–8%). Of 37 total variants in the meta-analysis, 7 (18.9%) each were pathogenic and likely pathogenic; others were variants of unknown significance.

Conclusions

Significant variants in complement regulatory genes are rare in patients with anti-FH-associated aHUS. Irrespective of genetic defects, plasma exchanges and immunosuppression showed a statistical trend to improved outcomes.

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Acknowledgements

We gratefully acknowledge Dr. Marie-Agnes Dragon-Durey (Hopital European Georges Pompidou, France) for helping establish the facility. We thank Dr. David Kavanagh (National Renal Complement Therapeutics Centre, UK) for suggestions to improve the manuscript.

Funding

Funding support by Indo-French Centre for the Promotion of Advanced Research (CEFIPRA) [IFC/A/4703–1/2015/1562; IFC/Network 1/2185]; Department of Biotechnology, Government of India [BT/PR14651/MED/30/566/2010]; Indian Council of Medical Research [Advanced Center for Research in Pediatric Kidney Diseases; 5/7/1090/2013-RHN]; Department of Science and Technology, Government of India [EMR12016/002781]; and the All India Institute of Medical Sciences, New Delhi [A-386].

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Authors and Affiliations

  1. Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India

    Priyanka Khandelwal, Mamta Puraswani, Bahadur Singh Gurjar, Aditi Sinha, Pankaj Hari & Arvind Bagga

  2. Genomics and Molecular Medicine, CSIR Institute of Genomics and Integrative Biology, Delhi, India

    Aditi Joshi, Aradhana Mathur & Mohammed Faruq

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  1. Priyanka Khandelwal
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467_2022_5862_MOESM2_ESM.pdf

Supplementary file2 Supplementary Figure S1 Flow chart showing variant prioritization. Variants were filtered by focusing on nonsynonymous variants affecting coding region genes. Rare variants have minor allele frequency < 0.1% in 1000 Genome and Genome aggregation database. Predicted pathogenic variants include stop-gain mutations, indels, or missense variants with CADD score > 10 and/or those predicted pathogenic by Polyphen2. Variants below a depth of 40X and allele balance of < 0.3 did not get validated on Sanger, and therefore were excluded on additional hard filtering. The final dataset is comprised of 20 variants in all genes. CADD, Combined Annotation-Dependent Depletion; UTR, untranslated region (PDF 388 KB)

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Khandelwal, P., Joshi, A., Mathur, A. et al. Variants in complement genes are uncommon in patients with anti-factor H autoantibody-associated atypical hemolytic uremic syndrome. Pediatr Nephrol 38, 2659–2668 (2023). https://doi.org/10.1007/s00467-022-05862-1

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