scholarly journals Cases in Precision Medicine: APOL1 and Genetic Testing in the Evaluation of Chronic Kidney Disease and Potential Transplant

2019 ◽  
Vol 171 (9) ◽  
pp. 659 ◽  
Author(s):  
Y. Dana Neugut ◽  
Sumit Mohan ◽  
Ali G. Gharavi ◽  
Krzysztof Kiryluk
Keyword(s):  
Chronic Kidney Disease ◽  
Genetic Testing ◽  
Kidney Disease ◽  
Precision Medicine

P0066KIDNEYCODE: A GENETIC TESTING PROGRAM FOR PATIENTS WITH CHRONIC KIDNEY DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Prasad Devarajan ◽  
Geoffrey Block ◽  
Keisha Gibson ◽  
Jim McKay ◽  
Colin Meyer ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Genetic Testing ◽  
Kidney Disease ◽  
Exome Sequencing ◽  
Polycystic Kidney Disease ◽  
Whole Exome Sequencing ◽  
Alport Syndrome ◽  
Polycystic Kidney ◽  
Accuracy And Precision ◽  
Whole Exome

Abstract Background and Aims Knowledge about genetic causes of chronic kidney disease (CKD) is one of the key gaps in global kidney research and recent International Society of Nephrology recommendations encourage the adoption of genetic testing to enable a goal of providing precision medicine based on individual risk (1). A recent whole-exome sequencing study showed that genetic inheritance may be responsible for up to 10% of CKD diagnoses, many of which may be previously undiagnosed or mis-diagnosed (2). Continued advances in DNA sequencing technology have made genetic testing, even whole-exome sequencing, applicable to routine clinical diagnoses. In order to test the hypothesis that genetic testing can provide valuable information to increase the accuracy and precision of diagnosis in CKD, we designed a gene panel to prospectively provide genetic testing in a subset of patients with CKD defined by a specific set of inclusion criteria. Method Reata Pharmaceuticals is partnering with Invitae on a program called KidneyCode, which provides no-charge genetic testing to enable diagnosis of three specific rare monogenic causes of CKD: Alport syndrome (AS), autosomal dominant polycystic kidney disease (ADPKD) due to PKD2 mutations, and focal segmental glomerulosclerosis (FSGS), as well as detection of variants in one of the autosomal recessive polycystic kidney disease gene, PKHD1. Invitae’s renal disease panel includes 17 genes (ACTN4, ANLN, CD2AP, COL4A3, COL4A4, COL4A5, CRB2, HNF1A, INF2, LMX1B, MYO1E, NPHS1, NPHS2, PAX2, PKD2, PKHD1, and TRPC6), and its assay includes both full-gene sequencing and intragenic deletion/duplication analysis using next-generation sequencing (NGS). The assay targets the coding exons and flanking 10bp of intronic sequences. Invitae’s method of variant classification uses a systematic process for assessing evidence based on guidelines published by the American College of Medical Genetics (3). Patients in the US at risk for hereditary CKD (eGFR ≤ 90 mL/min/1.73m2 plus hematuria or a family history of CKD) or with a known diagnosis of AS or FSGS are eligible. Family members of those with suspected or known AS or FSGS are also eligible. All participants in the KidneyCode program have access to genetic counseling follow-up at no additional charge. Results In the first five months of the KidneyCode program, 152 genetic tests have been completed. A genetic variant was reported in 87 patients. Of those 87 patients, 67 patients had 75 variants in COL4A3, 4, or 5 genes (34 Pathogenic/Likely Pathogenic (P/LP), 41 Variants of Uncertain Significance (VUS)), 20 patients had 24 variants in genes associated with FSGS (3 P/LP, 21 VUS), 15 patients had 20 variants in PKHD1 (1 P/LP, 19 VUS), and 2 patients had variants in PKD2 (1 P/LP, 1 VUS). Of the 34 patients with Pathogenic or Likely Pathogenic COL4A variants, 19 reported a previous diagnosis of Alport syndrome. Other diagnoses in patients with COL4A mutations included FSGS, thin basement membrane disease, and familial hematuria. Extra-renal manifestations such as hearing loss and eye disease were reported in 7 of the 34 patients with COL4A variants. Conclusion Initial results with the KidneyCode panel demonstrate the utility of NGS and support the hypothesis that combining genetic testing with clinical presentation and medical history can significantly improve accuracy and precision of diagnosis in patients with hereditary CKD.

scholarly journals Make Precision Medicine Work for Chronic Kidney Disease

2016 ◽  
Vol 26 (2) ◽  
pp. 101-107 ◽  
Author(s):  
Ling Sun ◽  
Lu-Xi Zou ◽  
Mao-Jie Chen
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Precision Medicine

scholarly journals Willingness to Participate in a National Precision Medicine Cohort: Attitudes of Chronic Kidney Disease Patients at a Cleveland Public Hospital

2018 ◽  
Vol 8 (3) ◽  
pp. 21 ◽  
Author(s):  
Jessica Cooke Bailey ◽  
Dana Crawford ◽  
Aaron Goldenberg ◽  
Anne Slaven ◽  
Julie Pencak ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Precision Medicine ◽  
Public Hospital ◽  
Willingness To Participate

Family History is Important to Identify Patients with Monogenic Causes of Adult-Onset Chronic Kidney Disease

Nephron ◽  
2021 ◽  
pp. 1-9
Author(s):  
Jeff Granhøj ◽  
Birgitte Tougaard ◽  
Dorte L. Lildballe ◽  
Maria Rasmussen
Keyword(s):  
Chronic Kidney Disease ◽  
Genetic Testing ◽  
Family History ◽  
Kidney Disease ◽  
Case Series ◽  
Genetic Diagnostics ◽  
Compound Heterozygous ◽  
Adult Onset ◽  
Disease Case ◽  
The Family

Monogenic causes of chronic kidney disease (CKD) are more prevalent in adults than previously thought, as causative gene variants are found in almost 10% of unselected patients with CKD. Even so, genetic testing in patients with adult-onset CKD is uncommon in clinical practice and the optimal criteria for patient selection remain unclear. A family history of kidney disease emerges as one marker associated with a high diagnostic yield of genetic testing. We present 3 cases of adult-onset CKD with underlying monogenic causes exemplifying different modes of inheritance. Case 1 is a 60-year-old male with slowly progressive CKD initially ascribed to hypertension and diabetes despite a family history with several affected first-degree relatives. A pathogenic <i>MUC1</i> variant was found, and thus we identified the first Danish family of <i>MUC1</i>-associated autosomal dominant tubulointerstitial kidney disease. Case 2 is a 40-year-old female with nephrocalcinosis, nephrolithiasis, and unexplainable hypercalcemia consistent with vitamin D intoxication. The family history indicated autosomal recessive inheritance, and genetic testing revealed 2 pathogenic <i>CYP24A1</i> variants in compound heterozygous form associated with idiopathic infantile hypercalcemia. Case 3 is a 50-year-old male with microscopic hematuria, proteinuria, and hearing loss. Electron microscopy of renal biopsy showed thin basal membrane syndrome, and the family history indicated X-linked inheritance. A novel missense variant in <i>COL4A5</i> was identified, suggesting an atypical late-onset form of X-linked Alport syndrome. This case series illustrates the heterogeneous presentations of monogenic kidney disease in adults and emphasizes the importance of family history for initiating genetic testing to identify underlying monogenic causation. Moreover, we discuss the potential impact of genetic diagnostics on patient management and genetic family counseling.

GSTM1 Gene, Diet, and Kidney Disease: Implication for Precision Medicine?: Recent Advances in Hypertension

Hypertension ◽  
2021 ◽  
Author(s):  
Thu H. Le
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Precision Medicine ◽  
Disease Progression ◽  
Angiotensin Receptor Blockers ◽  
The United States ◽  
Cruciferous Vegetables ◽  
Related Factor ◽  
Environment Interaction

In the United States, the prevalence of chronic kidney disease in adults is ≈14%. The mainstay of therapy for chronic kidney disease is angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, but many patients with chronic kidney disease still progress to end-stage kidney disease. Increased oxidative stress is a major molecular underpinning of chronic kidney disease progression. In humans, a common deletion variant of the glutathione-S-transferase μ-1 ( GSTM1 ) gene, the GSTM1 null allele ( GSTM1(0 )), results in decreased GSTM1 enzymatic activity and is associated with higher levels of oxidative stress. GSTM1 belongs to the superfamily of GSTs that are phase II antioxidant enzymes and are regulated by Nrf2 (nuclear factor erythroid 2-related factor 2). Cruciferous vegetables in general, and broccoli in particular, are rich in glucoraphanin, a precursor of sulforaphane that has been shown to have protective effects against oxidative damage through the activation of Nrf2. This review will highlight recent human and animal studies implicating the role of GSTM1 deficiency in hypertension and kidney disease, and its impact on the effects of cruciferous vegetables on kidney injury and disease progression, illustrating the significance of gene and environment interaction and a potential for targeted precision medicine in the treatment of kidney disease.

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