Diagnosis of monogenic chronic kidney diseases

Armstrong, Margaret E.; Thomas, Christie P.

doi:10.1097/mnh.0000000000000486

Cited by 24 publications

(15 citation statements)

References 50 publications

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“…With mapping of the human genome and advances in genetic sequencing technology, an increasing number of genetic causes of renal disease have been identified. 1 It has become evident that many genetic diseases are present in individuals without an apparent family history of kidney disease, often reflecting the nonrecognition of affected family members, possibly from variable or subtle disease expression or nonpenetrance. In addition, occasionally family history cannot be ascertained (adoptees) or be misleading (misattributed paternity).…”

Section: Introductionmentioning

confidence: 99%

Initial experience from a renal genetics clinic demonstrates a distinct role in patient management

Thomas

Freese

Ounda

et al. 2020

Genetics in Medicine

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Section: Introductionmentioning

confidence: 99%

Initial experience from a renal genetics clinic demonstrates a distinct role in patient management

Thomas

Freese

Ounda

et al. 2020

Genetics in Medicine

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“…Moreover, genetic testing is noninvasive and can shorten the diagnostic odyssey. Identification of a genetic diagnosis can play an important role in family planning, options for kidney transplantation, targeted surveillance of extra-renal features and can guide treatment and genetic counseling (Adams and Eng, 2018;Nestor et al, 2018;Armstrong and Thomas, 2019). Counseling and genetic testing can also be of importance for relatives of the patient with genetic CKD.…”

Section: Next Generation Sequencingmentioning

confidence: 99%

Diagnostic Yield of Next-Generation Sequencing in Patients With Chronic Kidney Disease of Unknown Etiology

et al. 2019

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Advances in next-generation sequencing (NGS) techniques, including whole exome sequencing, have facilitated cost-effective sequencing of large regions of the genome, enabling the implementation of NGS in clinical practice. Chronic kidney disease (CKD) is a major contributor to global burden of disease and is associated with an increased risk of morbidity and mortality. CKD can be caused by a wide variety of primary renal disorders. In about one in five CKD patients, no primary renal disease diagnosis can be established. Moreover, recent studies indicate that the clinical diagnosis may be incorrect in a substantial number of patients. Both the absence of a diagnosis or an incorrect diagnosis can have therapeutic implications. Genetic testing might increase the diagnostic accuracy in patients with CKD, especially in patients with unknown etiology. The diagnostic utility of NGS has been shown mainly in pediatric CKD cohorts, while emerging data suggest that genetic testing can also be a valuable diagnostic tool in adults with CKD. In addition to its implications for unexplained CKD, NGS can contribute to the diagnostic process in kidney diseases with an atypical presentation, where it may lead to reclassification of the primary renal disease diagnosis. So far, only a few studies have reported on the diagnostic yield of NGS-based techniques in patients with unexplained CKD. Here, we will discuss the potential diagnostic role of gene panels and whole exome sequencing in pediatric and adult patients with unexplained and atypical CKD.

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“…In this study, we identified a cytosine duplication within one of the VNTR sequences by SMRT sequencing combined with Sanger sequencing, which confirmed the existence of the MUC1 mutation. Subsequently, immunohistochemical staining of MUC1fs was found to be positive in renal tubular epithelial cells, which provided the further evidence of the MUC1 mutation 22,23 . Due to difficulties in sequencing the VNTR region of MUC1and the risk of renal biopsy in suspected patients with renal insufficiency, Živná M et al 14 developed an immunostaining method for MUC1fs in urinary exfoliated cells for screening of ADTKD-MUC1.…”

Section: Discussionmentioning

confidence: 83%

SMRT sequencing revealed to be an effective method for ADTKD-MUC1 diagnosis through follow-up analysis of a Chinese family

Wang

Rui

Dong

et al. 2020

Sci Rep

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We reported a large Chinese family diagnosed with autosomal dominant tubulointerstitial kidney disease caused by MUC1 mutation (ADTKD-MUC1). Cytosine duplication within a string of 7 cytosines in the variable-number tandem repeats (VNTR) region of the MUC1 gene was detected by long-read single-molecule real-time (SMRT) sequencing. MUC1 frameshift protein (MUC1fs) was found to be expressed in renal tubules and urinary exfoliated cells by pathological examination. The family, which consisted of 5 generations including 137 individuals, was followed for 5 years. Genetic testing was performed in thirty-four individuals, 17 of whom carried MUC1 mutations. The ADTKD-MUC1-affected individuals had an elevated incidence of hyperuricaemia without gout attack. Within five years, higher baseline levels of urinary α1-microglobulin were detected in affected individuals with rapidly progressing renal failure than in affected individuals with stable renal function, and the increases manifested even before increases in serum creatinine. This study demonstrates that SMRT sequencing is an effective method for the identification of MUC1 mutations. The pathological examination of MUC1fs expression in renal tissue and urinary exfoliated cells can contribute to early screening of family members suspected to be affected. It is suggested that affected individuals with elevated urinary α1microglobulin levels should be closely monitored for renal function. Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a hereditary disease characterized by progressive tubulointerstitial nephropathy that ultimately leads to end-stage renal disease (ESRD) 1-4. To date, four genes mutation which causes ADTKD have been identified: uromodulin (UMOD) 5 , mucin-1 (MUC1) 6 , renin (REN) 7 and hepatocyte nuclear factor 1β (HNF1B) 8. The disease forms caused by these mutations were named ADTKD-UMOD, ADTKD-MUC1, ADTKD-REN and ADTKD-HNF1B, respectively. Recently, a SEC. 61A1 mutation was identified as a novel cause of ADTKD 9. The manifestations of ADTKD are nonspecific, including autosomal dominant inheritance, bland urinary sediment with absent or mild proteinuria, progressive kidney failure, and, in some cases, multiple small renal cysts 1-3,10,11. Renal histology shows interstitial fibrosis and tubular atrophy, varying degree of nephrosclerosis and arteriolar thickening. Immunofluorescence or immunostaining on the renal tissue is negative. Electron microscopy usually showed irregular width and lamelation of the glomerular basement membrane and particular the tubular basement membrane 2,12-14. The diagnosis of ADTKD-MUC1 depends on genetic analysis. The MUC1 gene, located on chromosome 1q21, contains 20-125 copies of a repetitive sequence of 60 basepair in the variable-number tandem repeats (VNTR) domain 13. Most MUC1 mutations are caused by duplication of a cytosine within a seven-cytosine stretch in the VNTR region that produces a frameshift muatation, resulting in MUC1 frameshift protein (MUC1fs) 6,14-16. In addition, mutations in other areas of ...

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Diagnosis of monogenic chronic kidney diseases

Cited by 24 publications

References 50 publications

Initial experience from a renal genetics clinic demonstrates a distinct role in patient management

Initial experience from a renal genetics clinic demonstrates a distinct role in patient management

Diagnostic Yield of Next-Generation Sequencing in Patients With Chronic Kidney Disease of Unknown Etiology

SMRT sequencing revealed to be an effective method for ADTKD-MUC1 diagnosis through follow-up analysis of a Chinese family

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