Whole-Exome Sequencing in Adults With Chronic Kidney Disease

A Pilot Study

Sneh Lata, Maddalena Marasa, Yifu Li, David A Fasel, Emily Groopman, Vaidehi Jobanputra, Hila Rasouly, Adele Mitrotti, Rik Westland, Miguel Verbitsky, Jordan Nestor, Lindsey M Slater, Vivette D'Agati, Marcin Zaniew, Anna Materna-Kiryluk, Francesca Lugani, Gianluca Caridi, Luca Rampoldi, Aditya Mattoo, Chad A Newton & 12 others Maya K Rao, Jai Radhakrishnan, Wooin Ahn, Pietro A Canetta, Andrew S Bomback, Gerald B Appel, Corinne Antignac, Glen S Markowitz, Christine K Garcia, Krzysztof Kiryluk, Simone Sanna-Cherchi, Ali G Gharavi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)100-109
Number of pages10
JournalAnnals of Internal Medicine
Volume168
Issue number2
DOIs
Publication statusPublished - Jan 16 2018

Fingerprint

Exome
Chronic Renal Insufficiency
Mutation
National Human Genome Research Institute (U.S.)
Fibrosis
Kidney
Donor Selection
Primary Myelofibrosis
Inborn Genetic Diseases
Telomere
National Institutes of Health (U.S.)
Tertiary Care Centers
Liver Cirrhosis
Sample Size
Population
Renal Insufficiency
Patient Care
Referral and Consultation
Transplantation
Research Personnel

Keywords

  • Adult
  • Exome/genetics
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • New York City
  • Renal Insufficiency, Chronic/genetics
  • Sequence Analysis, DNA/methods

Cite this

Lata, S., Marasa, M., Li, Y., Fasel, D. A., Groopman, E., Jobanputra, V., ... Gharavi, A. G. (2018). Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study. Annals of Internal Medicine, 168(2), 100-109. https://doi.org/10.7326/M17-1319

Whole-Exome Sequencing in Adults With Chronic Kidney Disease : A Pilot Study. / Lata, Sneh; Marasa, Maddalena; Li, Yifu; Fasel, David A; Groopman, Emily; Jobanputra, Vaidehi; Rasouly, Hila; Mitrotti, Adele; Westland, Rik; Verbitsky, Miguel; Nestor, Jordan; Slater, Lindsey M; D'Agati, Vivette; Zaniew, Marcin; Materna-Kiryluk, Anna; Lugani, Francesca; Caridi, Gianluca; Rampoldi, Luca; Mattoo, Aditya; Newton, Chad A; Rao, Maya K; Radhakrishnan, Jai; Ahn, Wooin; Canetta, Pietro A; Bomback, Andrew S; Appel, Gerald B; Antignac, Corinne; Markowitz, Glen S; Garcia, Christine K; Kiryluk, Krzysztof; Sanna-Cherchi, Simone; Gharavi, Ali G.

In: Annals of Internal Medicine, Vol. 168, No. 2, 16.01.2018, p. 100-109.

Research output: Contribution to journalArticle

Lata, S, Marasa, M, Li, Y, Fasel, DA, Groopman, E, Jobanputra, V, Rasouly, H, Mitrotti, A, Westland, R, Verbitsky, M, Nestor, J, Slater, LM, D'Agati, V, Zaniew, M, Materna-Kiryluk, A, Lugani, F, Caridi, G, Rampoldi, L, Mattoo, A, Newton, CA, Rao, MK, Radhakrishnan, J, Ahn, W, Canetta, PA, Bomback, AS, Appel, GB, Antignac, C, Markowitz, GS, Garcia, CK, Kiryluk, K, Sanna-Cherchi, S & Gharavi, AG 2018, 'Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study', Annals of Internal Medicine, vol. 168, no. 2, pp. 100-109. https://doi.org/10.7326/M17-1319
Lata S, Marasa M, Li Y, Fasel DA, Groopman E, Jobanputra V et al. Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study. Annals of Internal Medicine. 2018 Jan 16;168(2):100-109. https://doi.org/10.7326/M17-1319
Lata, Sneh ; Marasa, Maddalena ; Li, Yifu ; Fasel, David A ; Groopman, Emily ; Jobanputra, Vaidehi ; Rasouly, Hila ; Mitrotti, Adele ; Westland, Rik ; Verbitsky, Miguel ; Nestor, Jordan ; Slater, Lindsey M ; D'Agati, Vivette ; Zaniew, Marcin ; Materna-Kiryluk, Anna ; Lugani, Francesca ; Caridi, Gianluca ; Rampoldi, Luca ; Mattoo, Aditya ; Newton, Chad A ; Rao, Maya K ; Radhakrishnan, Jai ; Ahn, Wooin ; Canetta, Pietro A ; Bomback, Andrew S ; Appel, Gerald B ; Antignac, Corinne ; Markowitz, Glen S ; Garcia, Christine K ; Kiryluk, Krzysztof ; Sanna-Cherchi, Simone ; Gharavi, Ali G. / Whole-Exome Sequencing in Adults With Chronic Kidney Disease : A Pilot Study. In: Annals of Internal Medicine. 2018 ; Vol. 168, No. 2. pp. 100-109.
@article{539cec8b9acf4b1480470be55fa1af64,
title = "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.",
keywords = "Adult, Exome/genetics, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, New York City, Renal Insufficiency, Chronic/genetics, Sequence Analysis, DNA/methods",
author = "Sneh Lata and Maddalena Marasa and Yifu Li and Fasel, {David A} and Emily Groopman and Vaidehi Jobanputra and Hila Rasouly and Adele Mitrotti and Rik Westland and Miguel Verbitsky and Jordan Nestor and Slater, {Lindsey M} and Vivette D'Agati and Marcin Zaniew and Anna Materna-Kiryluk and Francesca Lugani and Gianluca Caridi and Luca Rampoldi and Aditya Mattoo and Newton, {Chad A} and Rao, {Maya K} and Jai Radhakrishnan and Wooin Ahn and Canetta, {Pietro A} and Bomback, {Andrew S} and Appel, {Gerald B} and Corinne Antignac and Markowitz, {Glen S} and Garcia, {Christine K} and Krzysztof Kiryluk and Simone Sanna-Cherchi and Gharavi, {Ali G}",
year = "2018",
month = "1",
day = "16",
doi = "10.7326/M17-1319",
language = "English",
volume = "168",
pages = "100--109",
journal = "Annals of Internal Medicine",
issn = "0003-4819",
publisher = "American College of Physicians",
number = "2",

}

TY - JOUR

T1 - Whole-Exome Sequencing in Adults With Chronic Kidney Disease

T2 - A Pilot Study

AU - Lata, Sneh

AU - Marasa, Maddalena

AU - Li, Yifu

AU - Fasel, David A

AU - Groopman, Emily

AU - Jobanputra, Vaidehi

AU - Rasouly, Hila

AU - Mitrotti, Adele

AU - Westland, Rik

AU - Verbitsky, Miguel

AU - Nestor, Jordan

AU - Slater, Lindsey M

AU - D'Agati, Vivette

AU - Zaniew, Marcin

AU - Materna-Kiryluk, Anna

AU - Lugani, Francesca

AU - Caridi, Gianluca

AU - Rampoldi, Luca

AU - Mattoo, Aditya

AU - Newton, Chad A

AU - Rao, Maya K

AU - Radhakrishnan, Jai

AU - Ahn, Wooin

AU - Canetta, Pietro A

AU - Bomback, Andrew S

AU - Appel, Gerald B

AU - Antignac, Corinne

AU - Markowitz, Glen S

AU - Garcia, Christine K

AU - Kiryluk, Krzysztof

AU - Sanna-Cherchi, Simone

AU - Gharavi, Ali G

PY - 2018/1/16

Y1 - 2018/1/16

N2 - 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.

AB - 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.

KW - Adult

KW - Exome/genetics

KW - Female

KW - Genetic Predisposition to Disease

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - New York City

KW - Renal Insufficiency, Chronic/genetics

KW - Sequence Analysis, DNA/methods

U2 - 10.7326/M17-1319

DO - 10.7326/M17-1319

M3 - Article

VL - 168

SP - 100

EP - 109

JO - Annals of Internal Medicine

JF - Annals of Internal Medicine

SN - 0003-4819

IS - 2

ER -