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Promises and pitfalls of whole-exome sequencing exemplified by a nephrotic syndrome family

  • Mara Sanches GuaragnaEmail author
  • Anna Cristina Gervásio de Brito Lutaif
  • Marcela Lopes de Souza
  • Andréa Trevas Maciel-Guerra
  • Vera Maria Santoro Belangero
  • Gil Guerra-Júnior
  • Maricilda Palandi de Mello
Original Article

Abstract

High-throughput techniques such as whole-exome sequencing (WES) show promise for the identification of candidate genes that underlie Mendelian diseases such as nephrotic syndrome (NS). These techniques have enabled the identification of a proportion of the approximately 54 genes associated with NS. However, the main pitfall of using WES in clinical and research practice is the identification of multiple variants, which hampers interpretation during downstream analysis. One useful strategy is to evaluate the co-inheritance of rare variants in affected family members. Here, we performed WES of a patient with steroid-resistant NS (SRNS) and intermittent microhematuria. Currently, 15 years after kidney transplantation, this patient presents normal kidney function. The patient was found to be homozygous for a rare MYO1E stop-gain variant, and was heterozygous for rare variants in NS-associated genes, COL4A4, KANK1, LAMB2, ANLN, E2F3, and APOL1. We evaluated the presence or absence of these variants in both parents and 11 siblings, three of whom exhibited a milder phenotype of the kidney disease. Analysis of variant segregation in the family, indicated the MYO1E stop-gain variant as the putative causal variant underlying the kidney disease in the patient and two of her affected sisters. Two secondary variants in COL4A4—identified in some other affected family members—require further functional studies to determine whether they play a role in the development of microhematuria in affected family members. Our data illustrate the difficulties in distinguishing the causal pathogenic variants from incidental findings after WES-based variant analysis, especially in heterogenous genetic conditions, such as NS.

Keywords

MYO1E Stop-gain variant Steroid-resistant nephrotic syndrome Whole-exome sequencing Incidental findings Kidney disease 

Notes

Acknowledgements

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP—2015/20502-6 to MPdeM, FAPESP—2013/24088-4 to MSG) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq—441506/2014-3 to GG-J).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

438_2019_1609_MOESM1_ESM.docx (5.7 mb)
Supplementary material 1 (DOCX 5805 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory of Human Molecular Genetics, Center for Molecular Biology and Genetic Engineering (CBMEG)State University of Campinas, UNICAMPCampinasBrazil
  2. 2.Integrated Center of Pediatric Nephrology (CIN), Department of Pediatrics, School of Medical Sciences (FCM)State University of Campinas, UNICAMPCampinasBrazil
  3. 3.Department of Medical Genetics, School of Medical Sciences (FCM)UNICAMPCampinasBrazil
  4. 4.Department of Pediatrics, School of Medical Sciences (FCM)UNICAMPCampinasBrazil
  5. 5.Growth and Development Laboratory, Center for Investigation in Pediatrics (CIPED), School of Medical Sciences (FCM)UNICAMPCampinasBrazil

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