Abstract
Background
Individuals with proteinuria in association with hypoalbuminemia, edema, and hyperlipidemia are considered as having nephrotic syndrome (NS). NS is the most common kidney disease seen in the paediatric age group. NS is usually classified into steroid resistant nephrotic syndrome (SRNS) and steroid sensitive nephrotic syndrome (SSNS). More than 58 genes have been identified as a monogenic cause of SRNS, however, the genetic architecture of childhood SSNS remains poorly understood.
Methods
Here in this study, we performed sequencing of 66 NS candidate genes followed by whole genome SNP genotyping and whole exome sequencing in SSNS families with multiple affected individuals.
Results
NS candidate genes sequencing did not identify any pathogenic variant in the known genes. Homozygosity mapping based on an autosomal recessive model failed to detect any shared loss of heterozygosity region in the genome. An unbiased and hypothesis-free exome data analysis identified a missense variant (c.383G>A; p.Arg128Gln) in the CENPI gene. Sanger sequencing of both parents, unaffected and affected individuals confirmed an X-linked inheritance pattern of the variant (c.383G>A) with SSNS phenotype. The variant (c.383G>A) is very rare and is potentially damaging.
Conclusion
Collectively, these observations suggest that a specific pathogenic link between SSNS development and alteration in CENPI exists. However, human mutations in CENPI causing SSNS have not been reported hitherto. Identification of genetic defects underlying SSNS will help in understanding the precise aetiology of SSNS and improved management of children with NS.
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Acknowledgements
We are thankful to study participants for their cooperation throughout the study.
Funding
This research was supported by the Strategic Technologies Programs of the National Plan for Science, Technology and Innovation (MAARIFAH) in the Kingdom of Saudi Arabia; Grant number 13‑MED2088‑05.
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HMA, MAS, RS recruited patients and performed clinical phenotyping; EA and JAH performed Sanger sequencing and segregation analysis; KR performed SNP genotyping data analysis; SB designed the study, analysed exome data and wrote the manuscript. All authors have seen the final draft.
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All procedures performed in the present study were approved by The Ethical Review Committee of Taibah University (Medina, Saudi Arabia; approval no. TU‑REC‑2016018) and were also in accordance with the Declaration of Helsinki. Written informed consent was obtained from all individual participants or the guardians of underage participants included in the study.
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Basit, S., Al-Edressi, H.M., Sairafi, M.H. et al. Centromere protein I (CENPI) is a candidate gene for X-linked steroid sensitive nephrotic syndrome. J Nephrol 33, 763–769 (2020). https://doi.org/10.1007/s40620-019-00692-1
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DOI: https://doi.org/10.1007/s40620-019-00692-1