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, Jorda Nestor, Lindsey M. Slater, Vivette D'Agati, Marcin Zaniew, Anna Materna-Kiryluk, Francesca Lugani, Gianluca Caridi, Luca Rampoldi, Aditya Mattoo, Chad A. NewtonMaya 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

35 Citations (Scopus)

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.

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

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Exome
Chronic Renal Insufficiency
Mutation
Fibrosis
Donor Selection
Primary Myelofibrosis
Inborn Genetic Diseases
Telomere
Tertiary Care Centers
Liver Cirrhosis
Sample Size
Population
Renal Insufficiency
Patient Care
Referral and Consultation
Transplantation
Breast Neoplasms
Hypertension
Phenotype
Kidney

ASJC Scopus subject areas

  • Internal Medicine

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, Jorda; 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, Jorda ; 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.
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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.",
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 Jorda 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.}",
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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, Jorda

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.

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