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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Guaragna, Mara Sanches [1] ; de Brito Lutaif, Anna Cristina Gervasio [2] ; de Souza, Marcela Lopes [1] ; Maciel-Guerra, Andrea Trevas [3] ; Belangero, Vera Maria Santoro [2, 4] ; Guerra-Junior, Gil [4, 5] ; de Mello, Maricilda Palandi [1]
Total Authors: 7
[1] Univ Estadual Campinas, Ctr Mol Biol & Genet Engn CBMEG, UNICAMP, Lab Human Mol Genet, Caixa Postal 6010, BR-13083875 Campinas, SP - Brazil
[2] Univ Estadual Campinas, UNICAMP, Sch Med Sci FCM, Integrated Ctr Pediat Nephrol CIN, Dept Pediat, Campinas - Brazil
[3] Univ Estadual Campinas, Sch Med Sci FCM, Dept Med Genet, Campinas, SP - Brazil
[4] Univ Estadual Campinas, Sch Med Sci FCM, Dept Pediat, Campinas, SP - Brazil
[5] Univ Estadual Campinas, Sch Med Sci FCM, Ctr Invest Pediat CIPED, Growth & Dev Lab, Campinas, SP - Brazil
Total Affiliations: 5
Document type: Journal article
Source: Molecular Genetics and Genomics; v. 295, n. 1, p. 135-142, JAN 2020.
Web of Science Citations: 0

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. (AU)

FAPESP's process: 13/24088-4 - EEstablishment of Exome Sequencing as a Resarch Tool for Screening Genes Related to Nephrotic Syndrome in Brazilian Children
Grantee:Mara Sanches Guaragna
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 15/20502-6 - Whole Exome Sequencing in Brazilian Children and Adolescents with Steroid Resistant Nephrotic Syndrome
Grantee:Maricilda Palandi de Mello
Support type: Regular Research Grants