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Targeted exome sequencing in anti-factor H antibody negative HUS reveals multiple variations

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Abstract

Background

Genetic susceptibility to atypical hemolytic uremic syndrome (aHUS) may lie within genes regulating or activating the alternate complement and related pathways converging on endothelial cell activation.

Methods

We tested 32 Indian patients of aHUS negative for antibodies to complement factor H for genetic variations in a panel of 15 genes, i.e., CFH, CFHR1-5, CFI, CFB, C3, CD46, MASP2, DGKE, ADAMTS13, THBD and PLG using next-generation DNA sequencing and for copy number variation in CFHR1-3.

Results

Despite absence of a public database of exome variations in the Indian population and limited functional studies, we could establish a genetic diagnosis in 6 (18.8%) patients using a stringent scheme of prioritization. One patient carried a likely pathogenic variation. The number of patients carrying possibly pathogenic variation was as follows: 1 variation: 5 patients, 2 variations: 9 patients, 3 variations: 5 patients, 4 variations: 9 patients, 5 variations: 2 patients and 6 variations: 2 patients. Homozygous deletion of CFHR1-3 was present in five patients; none of these carried a diagnostic genetic variation. Patients with or without diagnostic variation did not differ significantly in terms of enrichment of genetic variations that were rare/novel or predicted deleterious, or for possible environmental triggers.

Conclusion

We conclude that genetic testing for multiple genes in patients with aHUS negative for anti-FH antibodies reveals multiple candidate variations that require prioritization. Population data on variation frequency of the Indian population and supportive functional studies are likely to improve diagnostic yield.

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Acknowledgements

The authors wish to acknowledge the contributions of the following colleagues: Savita Saini from the Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi; Arti Yadav, Jyotsna Singh, and Debasis Dash from the CSIR-Institute of Genomics and Integrative Biology, New Delhi.

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Authors and Affiliations

  1. Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India

    R. W. Thergaonkar, Mamta Puraswani, Himanshi Saini, Aditi Sinha, Pankaj Hari & Arvind Bagga

  2. CSIR-Institute of Genomics and Integrative Biology, New Delhi, India

    Ankita Narang, Pradeep Tiwari, Binuja Varma & Mitali Mukerji

  3. National Institute of Immunology, New Delhi, India

    Bahadur Singh Gurjar

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  1. R. W. Thergaonkar
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Correspondence to Arvind Bagga.

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Conflict of interest

There are no conflicts of interest.

Funding

The study was supported by Centre Franco-Indien pour la Promotion de la Recherche Avancée (CEFIPRA) vide Project Code no. 4703-1.

Human and animal rights

The study was approved by the Institute Ethics Committee vide IEC/NP-162/10.04.2015.

Informed consent

Informed consent was obtained from all participants. Identifying details of the participants have not been included in the manuscript.

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Thergaonkar, R.W., Narang, A., Gurjar, B.S. et al. Targeted exome sequencing in anti-factor H antibody negative HUS reveals multiple variations. Clin Exp Nephrol 22, 653–660 (2018). https://doi.org/10.1007/s10157-017-1478-6

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  • DOI: https://doi.org/10.1007/s10157-017-1478-6

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