scholarly journals Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome

2017 ◽  
Vol 13 (1) ◽  
pp. 53-62 ◽  
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.

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

Nephron ◽  
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.

scholarly journals Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome

2019 ◽  
Vol 15 (1) ◽  
pp. 89-100 ◽  
Author(s):  
Samuela Landini ◽  
Benedetta Mazzinghi ◽  
Francesca Becherucci ◽  
Marco Allinovi ◽  
Aldesia Provenzano ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Signs ◽  
Long Term Outcome ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Steroid Sensitive

Background and objectivesNephrotic syndrome is a typical presentation of genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that extended genetic testing followed by reverse phenotyping would increase the diagnostic rate for these patients.Design, setting, participants, & measurementsAll patients diagnosed with nephrotic syndrome and referred to our center between 2000 and 2018 were assessed in this retrospective study. When indicated, whole-exome sequencing and in silico filtering of 298 genes related to CKD were combined with subsequent reverse phenotyping in patients and families. Pathogenic variants were defined according to current guidelines of the American College of Medical Genetics.ResultsA total of 111 patients (64 steroid-resistant and 47 steroid-sensitive) were included in the study. Not a single pathogenic variant was detected in the steroid-sensitive group. Overall, 30% (19 out of 64) of steroid-resistant patients had pathogenic variants in podocytopathy genes, whereas a substantial number of variants were identified in other genes, not commonly associated with isolated nephrotic syndrome. Reverse phenotyping, on the basis of a personalized diagnostic workflow, permitted to identify previously unrecognized clinical signs of an unexpected underlying genetic nephropathy in a further 28% (18 out of 64) of patients. These patients showed similar multidrug resistance, but different long-term outcome, when compared with genetic podocytopathies.ConclusionsReverse phenotyping increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome.

scholarly journals Searching for the missing genetic determinants of hereditary breast cancer risk by whole-exome sequencing of BRCA-negative patients: new candidate genes USP39, SLIT3, CREB3

2021 ◽  
Vol 67 (1) ◽  
pp. 111-116
Author(s):  
Kirill Zagorodnev ◽  
Aleksandr Romanko ◽  
Uliy Gorgul ◽  
Aleksandr Ivantsov ◽  
Anna Sokolenko ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Hereditary Breast Cancer ◽  
Germ Line ◽  
Genetic Diagnosis ◽  
Clinical Signs ◽  
Causative Mutation ◽  
Whole Exome

The search for the new hereditary mutations and a precise molecular genetic diagnosis that determines the causative mutation in each specific case of hereditary breast cancer (BC) is a clinically important task since it helps to define the personal therapeutic approach and increase the effectiveness of preventive measures. Using whole-exome sequencing (WES) we analyzed the full spectrum of hereditary variations in 49 Russian patients with clinical signs of a hereditary disease which allowed us to compile a list of 229 candidate probably pathogenic germ-line variants. Then, the selected candidate mutations were validated by Sanger sequencing and molecular-epidemiological studies, the predisposing roles of three oncologically relevant mutations (USP39 c.*208G>C, SLIT3 p.Arg154Cys, and CREB3 p.Lys157Glu) were confirmed. Our candidate genes are first mentioned in connection with the hereditary risk of BC. The final proofs of the causative roles of these variants could be obtained through functional tests as well as via the analysis of the mutations segregation in BC families.

scholarly journals Identification of Two Novel Mutations in the ATM Gene from Patients with Ataxia-Telangiectasia by Whole Exome Sequencing

2020 ◽  
Vol 20 (7) ◽  
pp. 531-534
Author(s):  
Masoud Heidari ◽  
Morteza Soleyman-Nejad ◽  
Mohammad H. Taskhiri ◽  
Javad Shahpouri ◽  
Alireza Isazadeh ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Ataxia Telangiectasia ◽  
Direct Sequencing ◽  
Genetic Diagnosis ◽  
Cell Cycle Checkpoints ◽  
Causative Mutation ◽  
Novel Mutations ◽  
Whole Exome ◽  
Atm Gene

Background: Ataxia telangiectasia (AT) is one of the most common autosomal recessive hereditary ataxia presenting in childhood. The responsible gene for AT designated ATM (AT, mutated) encodes a protein which is involved in cell cycle checkpoints and other responses to genotoxicity. We describe two novel disease-causing mutations in two unrelated Iranian families with Ataxiatelangiectasia. Methods: The probands including a 6-year-old female and an 18-year-old boy were diagnosed with Ataxia-telangiectasia among two different Iranian families. In this study, Whole-Exome Sequencing (WES) was employed for the detection of genetic changes in probands. The analysis of the cosegregation of the variants with the disease in families was conducted using PCR direct sequencing. Results: Two novel frameshift mutations, (c.4236_4236del p. Pro1412fs) and (c.8907T>G p. Tyr2969Ter) in the ataxia telangiectasia mutated ATM gene were detected using Whole-Exome Sequencing (WES) in the probands. These mutations were observed in two separate A-T families. Conclusion: Next-generation sequencing successfully identified the causative mutation in families with ataxia-telangiectasia. These novel mutations in the ATM gene reported in the present study could assist genetic counseling, Preimplantation Genetic Diagnosis (PGD) and prenatal diagnosis (PND) of AT.

scholarly journals Exome sequencing in paediatric patients with movement disorders

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Anna Ka-Yee Kwong ◽  
Mandy Ho-Yin Tsang ◽  
Jasmine Lee-Fong Fung ◽  
Christopher Chun-Yu Mak ◽  
Kate Lok-San Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Genetic Diagnosis ◽  
Potential Treatment ◽  
Paediatric Patients ◽  
Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

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