The status quo and challenges of genetic diagnosis in children with steroid-resistant nephrotic syndrome

Background: Steroid-resistant nephrotic syndrome is a genetic disease with autosomal recessive inheritance pattern and symptoms such as proteinuria and hypoalbuminemia and rapid progress of kidney disease. Preimplantation genetic diagnosis is an option for couples who are at risk of affected pregnancy to have a healthy child. Objectives: This study aimed to develop a new PGD test for a couple who are heterozygous for a mutation in NPHS2 gene and have a son affected to steroid-resistant nephrotic syndrome. Methods: Variant detection by cycle sequencing and Multiplex fluorescent PCR for identification of flanking STR markers were used to investigate the status of the embryos. Results: Three out of six embryos were transferable from which one was transferred and resulted in the birth of a healthy boy. Conclusions: We recommend increasing the number of the STR markers to two at the downstream of the NPHS2 gene especially in cases that direct mutation analysis such as cycle sequencing is not applied.

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Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.04120417 ◽

2017 ◽

Vol 13 (1) ◽

pp. 53-62 ◽

Cited By ~ 62

Author(s):

Jillian K. Warejko ◽

Weizhen Tan ◽

Ankana Daga ◽

David Schapiro ◽

Jennifer A. Lawson ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Diagnosis ◽

Congenital Nephrotic Syndrome ◽

Causative Mutation ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Whole Exome ◽

Panel Sequencing

Background and objectivesSteroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families.Design, setting, participants, & measurementsThree hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes.ResultsIn 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome.ConclusionsWhole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

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Genetic Study in Korean Pediatric Patients with Steroid-Resistant Nephrotic Syndrome or Focal Segmental Glomerulosclerosis

Journal of Clinical Medicine ◽

10.3390/jcm9062013 ◽

2020 ◽

Vol 9 (6) ◽

pp. 2013

Author(s):

Eujin Park ◽

Chung Lee ◽

Nayoung K. D. Kim ◽

Yo Han Ahn ◽

Young Seo Park ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Focal Segmental Glomerulosclerosis ◽

Detection Rate ◽

Pediatric Patients ◽

Mutation Detection ◽

Genetic Diagnosis ◽

Mutation Detection Rate ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Segmental Glomerulosclerosis

Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage renal disease (ESRD) in childhood and is mostly associated with focal segmental glomerulosclerosis (FSGS). More than 50 monogenic causes of SRNS or FSGS have been identified. Recently, the mutation detection rate in pediatric patients with SRNS has been reported to be approximately 30%. In this study, genotype-phenotype correlations in a cohort of 291 Korean pediatric patients with SRNS/FSGS were analyzed. The overall mutation detection rate was 43.6% (127 of 291 patients). WT1 was the most common causative gene (23.6%), followed by COQ6 (9.4%), NPHS1 (8.7%), NUP107 (7.1%), and COQ8B (6.3%). Mutations in COQ6, NUP107, and COQ8B were more frequently detected, and mutations in NPHS2 were less commonly detected in this cohort than in study cohorts from Western countries. The mutation detection rate was higher in patients with congenital onset, those who presented with proteinuria or chronic kidney disease/ESRD, and those who did not receive steroid treatment. Genetic diagnosis in patients with SRNS provides not only definitive diagnosis but also valuable information for decisions on treatment policy and prediction of prognosis. Therefore, further genotype-phenotype correlation studies are required.

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Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: a high proportion of causative variants in NUP93

Pediatric Nephrology ◽

10.1007/s00467-018-3950-2 ◽

2018 ◽

Vol 33 (8) ◽

pp. 1347-1363 ◽

Cited By ~ 10

Author(s):

Martin Bezdíčka ◽

Šárka Štolbová ◽

Tomáš Seeman ◽

Ondřej Cinek ◽

Michal Malina ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Genetic Diagnosis ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome

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Faculty Opinions recommendation of Tacrolimus: a new therapy for steroid-resistant nephrotic syndrome in children.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1104725.560794 ◽

2008 ◽

Author(s):

Neil Turner

Keyword(s):

Nephrotic Syndrome ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

New Therapy

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A rare cause of steroid-resistant nephrotic syndrome in a child: Answers

Pediatric Nephrology ◽

10.1007/s00467-019-04385-6 ◽

2019 ◽

Vol 35 (4) ◽

pp. 621-623

Author(s):

Lale Guliyeva ◽

Yılmaz Tabel ◽

Ali Düzova ◽

Nusret Akpolat ◽

Seza Özen ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome

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Whole-Exome Sequencing Solved over 2-Decade Kidney Disease Enigma

Nephron ◽

10.1159/000514293 ◽

2021 ◽

pp. 1-6

Author(s):

Suramath Isaranuwatchai ◽

Ankanee Chanakul ◽

Chupong Ittiwut ◽

Chalurmpon Srichomthong ◽

Vorasuk Shotelersuk ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Kidney Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Treatment Plan ◽

Unknown Etiology ◽

Pediatric Case ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Whole Exome

Chronic kidney disease of unknown etiology (CKDu) has been a problem in renal practice as indefinite diagnosis may lead to inappropriate management. Here, we report a 54-year-old father diagnosed with CKDu at 33 years old and his 8-year-old son with steroid-resistant nephrotic syndrome. Using whole-exome sequencing, both were found to be heterozygous for c.737G>A (p.Arg246Gln) in LMX1B. The diagnosis of LMX1B-associated nephropathy has led to changes in the treatment plan with appropriate genetic counseling. The previously reported cases with this particular mutation were also reviewed. Most children with LMX1B-associated nephropathy had nonnephrotic proteinuria with normal renal function. Interestingly, our pediatric case presented with steroid-resistant nephrotic syndrome at 8 years old and progressed to ESRD requiring peritoneal dialysis at the age of 15 years. Our report emphasized the need of genetic testing in CKDu for definite diagnosis leading to precise management.

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