Whole-Exome Sequencing in Adults With Chronic Kidney Disease

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown.

Related collections

Most cited references 19

Record: found
Abstract: found
Article: not found

Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive.

Chad A Newton, Kiran Batra, Jose Torrealba … (2016)

Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals.115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed.Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%). Discordant interstitial lung disease diagnoses were found in affected individuals from 80% of families. Patients with TERC mutations were diagnosed at an earlier age than those with PARN mutations (51±11 years versus 64±8 years; p=0.03) and had a higher incidence of haematological comorbidities. The mean rate of forced vital capacity decline was 300 mL·year(-1) and the median time to death or transplant was 2.87 years. There was no significant difference in time to death or transplant for patients across gene mutation groups or for patients with a diagnosis of IPF versus a non-IPF diagnosis.Genetic mutations in telomere related genes lead to a variety of interstitial lung disease (ILD) diagnoses that are universally progressive.

0 comments Cited 122 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.

Agnieszka Bierzynska, Hugh McCarthy, Katrina Soderquest … (2017)

Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9-30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.

0 comments Cited 111 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair

Weibin Zhou, Edgar Otto, Andrew Cluckey … (2012)

SUMMARY Chronic kidney disease (CKD) represents a major health burden 1 . Its central feature of renal fibrosis is not well understood. By whole exome resequencing in a model disorder for renal fibrosis, nephronophthisis (NPHP), we identified mutations of Fanconi anemia-associated nuclease 1 (FAN1) as causing karyomegalic interstitial nephritis (KIN). Renal histology of KIN is indistinguishable from NPHP except for the presence of karyomegaly 2 . FAN1 has nuclease activity, acting in DNA interstrand crosslinking (ICL) repair within the Fanconi anemia pathway of DNA damage response (DDR) 3–6 . We demonstrate that cells from individuals with FAN1 mutations exhibit sensitivity to the ICL agent mitomycin C. However, they do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from patients with Fanconi anemia. We complement ICL sensitivity with wild type FAN1 but not mutant cDNA from individuals with KIN. Depletion of fan1 in zebrafish revealed increased DDR, apoptosis, and kidney cysts akin to NPHP. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms of renal fibrosis and CKD.

0 comments Cited 92 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Title: Annals of Internal Medicine

Abbreviated Title: Ann Intern Med

Publisher: American College of Physicians

ISSN (Print): 0003-4819

Publication date Created: January 16 2018

Publication date (Electronic): December 05 2017

Publication date (Print): January 16 2018

Volume: 168

Issue: 2

Page: 100

Affiliations

[1 ]Columbia University, New York, New York (S.L., M.M., Y.L., D.A.F., E.G., V.J., H.R., A.M., M.V., J.N., V.D., M.K.R., J.R., W.A., P.A.C., A.S.B., G.B.A., G.S.M., K.K., S.S., A.G.G.)

[2 ]Columbia University, New York, New York, and VU University Medical Center, Amsterdam, the Netherlands (R.W.)

[3 ]Nephrology Associates, Newark, Delaware (L.M.S.)

[4 ]Krysiewicza Children's Hospital, Poznań, Poland (M.Z.)

[5 ]Poznań University of Medical Sciences and Center for Medical Genetics GENESIS, Poznań, Poland (A.M.)

[6 ]IRCCS Giannina Gaslini Children's Hospital, Genova, Italy (F.L., G.C.)

[7 ]IRCCS San Raffaele Scientific Institute, Milan, Italy (L.R.)

[8 ]New York University School of Medicine, New York, New York (A.M.)

[9 ]University of Texas Southwestern Medical Center, Dallas, Texas (C.A.N., C.K.G.)

[10 ]French Institute of Health and Medical Research (INSERM) U1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, and Necker Hospital, Paris, France (C.A.)

Article

DOI: 10.7326/M17-1319

PMC ID: 5947852

PubMed ID: 29204651

SO-VID: f72b690a-747d-4b04-8dfd-fadfe00086d5

History

Data availability:

Comments

Comment on this article

scite_

Cited by 73

See all cited by

- Version 1
- Version 1

Whole-Exome Sequencing in Adults With Chronic Kidney Disease : A Pilot Study

Read this article at

Abstract

Related collections

Alternative approaches to Alzheimer's Disease

Most cited references 19

Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive.

Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.

FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair

Author and article information

Journal

Affiliations

Article

History

Comments

Comment on this article

Similar content 2,110

Cited by 73