Dataset Information

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

ABSTRACT:

Background

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.

Objective

To study the diagnostic utility of WES in a selected referral population of adults with CKD.

Design

Observational cohort.

Setting

A major academic medical center.

Patients

92 adults with CKD of unknown cause or familial nephropathy or hypertension.

Measurements

The diagnostic yield of WES and its potential effect on clinical management.

Results

Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands with tubulointerstitial fibrosis. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most identified cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy.

Limitation

The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population.

Conclusion

Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted.

Primary funding source

New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.

SUBMITTER: Lata S

PROVIDER: S-EPMC5947852 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Lata Sneh S Marasa Maddalena M Li Yifu Y Fasel David A DA Groopman Emily E Jobanputra Vaidehi V Rasouly Hila H Mitrotti Adele A Westland Rik R Verbitsky Miguel M Nestor Jordan J Slater Lindsey M LM D'Agati Vivette V Zaniew Marcin M Materna-Kiryluk Anna A Lugani Francesca F Caridi Gianluca G Rampoldi Luca L Mattoo Aditya A Newton Chad A CA Rao Maya K MK Radhakrishnan Jai J Ahn Wooin W Canetta Pietro A PA Bomback Andrew S AS Appel Gerald B GB Antignac Corinne C Markowitz Glen S GS Garcia Christine K CK Kiryluk Krzysztof K Sanna-Cherchi Simone S Gharavi Ali G AG

Annals of internal medicine 20171205 2

<h4>Background</h4>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.<h4>Objective</h4>To study the diagnostic utility of WES in a selected referral population of adults with CKD.<h4>Design</h4>Observational cohort.<h4>Setting</h4>A major academic medical c ...[more]

PMID: 29204651

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Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) is a condition usually caused by a single gene mutation and manifested by both renal and extrarenal features, eventually leading to end-stage renal disease (ESRD) by the median age of 60 years worldwide. Approximately 89% of ADPKD patients had either PKD1 or PKD2 gene mutations. The majority (85%) of the mutations are in the PKD1 gene, especially in the context of family history. Objectives: This study investigated the genetic basis and the undiscovered genes that are involved in ADPKD development among the Saudi population. Materials and Methods: In this study, 11 patients with chronic kidney disease were enrolled. The diagnosis of ADPKD was based on history and diagnostic images: CT images include enlargement of renal outlines, renal echogenicity, and presence of multiple renal cysts with dilated collecting ducts, loss of corticomedullary differentiation, and changes in GFR and serum creatinine levels. Next-generation whole-exome sequencing was conducted using the Ion Torrent PGM platform. Results: Of the 11 Saudi patients diagnosed with chronic kidney disease (CKD) and ADPKD, the most common heterozygote nonsynonymous variant in the PKD1 gene was exon15: (c.4264G > A). Two missense mutations were identified with a PKD1 (c.1758A > C and c.9774T > G), and one patient had a PKD2 mutation (c.1445T > G). Three detected variants were novel, identified at PKD1 (c.1758A > C), PKD2L2 (c.1364A > T), and TSC2 (deletion of a'a at the 3'UTR, R1680C) genes. Other variants in PKD1L1 (c.3813_381 4delinsTG) and PKD1L2 (c.404C > T) were also detected. The median age of end-stage renal disease for ADPK patients in Saudi Arabia was 30 years. Conclusion: This study reported a common variant in the PKD1 gene in Saudi patients with typical ADPKD. We also reported (to our knowledge) for the first time two novel missense variants in PKD1 and PKD2L2 genes and one indel mutation at the 3'UTR of the TSC2 gene. This study establishes that the reported mutations in the affected genes resulted in ADPKD development in the Saudi population by a median age of 30. Nevertheless, future protein-protein interaction studies to investigate the influence of these mutations on PKD1 and PKD2 functions are required. Furthermore, large-scale population-based studies to verify these findings are recommended.

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Dataset Information

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

Background

Objective

Design

Setting

Patients

Measurements

Results

Limitation

Conclusion

Primary funding source

Publications

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

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