Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies

Heon Yung Gee, Edgar A. Otto, Toby W. Hurd, Shazia Ashraf, Moumita Chaki, Andrew Cluckey, Virginia Vega-Warner, Pawaree Saisawat, Katrina A. Diaz, Humphrey Fang, Stefan Kohl, Susan J. Allen, Rannar Airik, Weibin Zhou, Gokul Ramaswami, Sabine Janssen, Clementine Fu, Jamie L. Innis, Stefanie Weber, Udo Vester & 22 others Erica E. Davis, Nicholas Katsanis, Hanan M. Fathy, Nikola Jeck, Gunther Klaus, Ahmet Nayir, Khawla A. Rahim, Ibrahim Al Attrach, Ibrahim Al Hassoun, Savas Ozturk, Dorota Drozdz, Udo Helmchen, John F. O'toole, Massimo Attanasio, Richard A. Lewis, Gudrun Nürnberg, Peter Nürnberg, Joseph Washburn, James Macdonald, Jeffrey W. Innis, Shawn Levy, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.

Original languageEnglish
Pages (from-to)880-887
Number of pages8
JournalKidney International
Volume85
Issue number4
DOIs
Publication statusPublished - 2014 Jan 1

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Cystic Kidney Diseases
Exome
Recessive Genes
Kidney
Chronic Renal Insufficiency
Rare Diseases
Genes
Mutation
Kidney Diseases
Causality
Chronic Disease
Ciliopathies

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Gee, H. Y., Otto, E. A., Hurd, T. W., Ashraf, S., Chaki, M., Cluckey, A., ... Hildebrandt, F. (2014). Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies. Kidney International, 85(4), 880-887. https://doi.org/10.1038/ki.2013.450
Gee, Heon Yung ; Otto, Edgar A. ; Hurd, Toby W. ; Ashraf, Shazia ; Chaki, Moumita ; Cluckey, Andrew ; Vega-Warner, Virginia ; Saisawat, Pawaree ; Diaz, Katrina A. ; Fang, Humphrey ; Kohl, Stefan ; Allen, Susan J. ; Airik, Rannar ; Zhou, Weibin ; Ramaswami, Gokul ; Janssen, Sabine ; Fu, Clementine ; Innis, Jamie L. ; Weber, Stefanie ; Vester, Udo ; Davis, Erica E. ; Katsanis, Nicholas ; Fathy, Hanan M. ; Jeck, Nikola ; Klaus, Gunther ; Nayir, Ahmet ; Rahim, Khawla A. ; Attrach, Ibrahim Al ; Hassoun, Ibrahim Al ; Ozturk, Savas ; Drozdz, Dorota ; Helmchen, Udo ; O'toole, John F. ; Attanasio, Massimo ; Lewis, Richard A. ; Nürnberg, Gudrun ; Nürnberg, Peter ; Washburn, Joseph ; Macdonald, James ; Innis, Jeffrey W. ; Levy, Shawn ; Hildebrandt, Friedhelm. / Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies. In: Kidney International. 2014 ; Vol. 85, No. 4. pp. 880-887.
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abstract = "Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.",
author = "Gee, {Heon Yung} and Otto, {Edgar A.} and Hurd, {Toby W.} and Shazia Ashraf and Moumita Chaki and Andrew Cluckey and Virginia Vega-Warner and Pawaree Saisawat and Diaz, {Katrina A.} and Humphrey Fang and Stefan Kohl and Allen, {Susan J.} and Rannar Airik and Weibin Zhou and Gokul Ramaswami and Sabine Janssen and Clementine Fu and Innis, {Jamie L.} and Stefanie Weber and Udo Vester and Davis, {Erica E.} and Nicholas Katsanis and Fathy, {Hanan M.} and Nikola Jeck and Gunther Klaus and Ahmet Nayir and Rahim, {Khawla A.} and Attrach, {Ibrahim Al} and Hassoun, {Ibrahim Al} and Savas Ozturk and Dorota Drozdz and Udo Helmchen and O'toole, {John F.} and Massimo Attanasio and Lewis, {Richard A.} and Gudrun N{\"u}rnberg and Peter N{\"u}rnberg and Joseph Washburn and James Macdonald and Innis, {Jeffrey W.} and Shawn Levy and Friedhelm Hildebrandt",
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Gee, HY, Otto, EA, Hurd, TW, Ashraf, S, Chaki, M, Cluckey, A, Vega-Warner, V, Saisawat, P, Diaz, KA, Fang, H, Kohl, S, Allen, SJ, Airik, R, Zhou, W, Ramaswami, G, Janssen, S, Fu, C, Innis, JL, Weber, S, Vester, U, Davis, EE, Katsanis, N, Fathy, HM, Jeck, N, Klaus, G, Nayir, A, Rahim, KA, Attrach, IA, Hassoun, IA, Ozturk, S, Drozdz, D, Helmchen, U, O'toole, JF, Attanasio, M, Lewis, RA, Nürnberg, G, Nürnberg, P, Washburn, J, Macdonald, J, Innis, JW, Levy, S & Hildebrandt, F 2014, 'Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies', Kidney International, vol. 85, no. 4, pp. 880-887. https://doi.org/10.1038/ki.2013.450

Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies. / Gee, Heon Yung; Otto, Edgar A.; Hurd, Toby W.; Ashraf, Shazia; Chaki, Moumita; Cluckey, Andrew; Vega-Warner, Virginia; Saisawat, Pawaree; Diaz, Katrina A.; Fang, Humphrey; Kohl, Stefan; Allen, Susan J.; Airik, Rannar; Zhou, Weibin; Ramaswami, Gokul; Janssen, Sabine; Fu, Clementine; Innis, Jamie L.; Weber, Stefanie; Vester, Udo; Davis, Erica E.; Katsanis, Nicholas; Fathy, Hanan M.; Jeck, Nikola; Klaus, Gunther; Nayir, Ahmet; Rahim, Khawla A.; Attrach, Ibrahim Al; Hassoun, Ibrahim Al; Ozturk, Savas; Drozdz, Dorota; Helmchen, Udo; O'toole, John F.; Attanasio, Massimo; Lewis, Richard A.; Nürnberg, Gudrun; Nürnberg, Peter; Washburn, Joseph; Macdonald, James; Innis, Jeffrey W.; Levy, Shawn; Hildebrandt, Friedhelm.

In: Kidney International, Vol. 85, No. 4, 01.01.2014, p. 880-887.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies

AU - Gee, Heon Yung

AU - Otto, Edgar A.

AU - Hurd, Toby W.

AU - Ashraf, Shazia

AU - Chaki, Moumita

AU - Cluckey, Andrew

AU - Vega-Warner, Virginia

AU - Saisawat, Pawaree

AU - Diaz, Katrina A.

AU - Fang, Humphrey

AU - Kohl, Stefan

AU - Allen, Susan J.

AU - Airik, Rannar

AU - Zhou, Weibin

AU - Ramaswami, Gokul

AU - Janssen, Sabine

AU - Fu, Clementine

AU - Innis, Jamie L.

AU - Weber, Stefanie

AU - Vester, Udo

AU - Davis, Erica E.

AU - Katsanis, Nicholas

AU - Fathy, Hanan M.

AU - Jeck, Nikola

AU - Klaus, Gunther

AU - Nayir, Ahmet

AU - Rahim, Khawla A.

AU - Attrach, Ibrahim Al

AU - Hassoun, Ibrahim Al

AU - Ozturk, Savas

AU - Drozdz, Dorota

AU - Helmchen, Udo

AU - O'toole, John F.

AU - Attanasio, Massimo

AU - Lewis, Richard A.

AU - Nürnberg, Gudrun

AU - Nürnberg, Peter

AU - Washburn, Joseph

AU - Macdonald, James

AU - Innis, Jeffrey W.

AU - Levy, Shawn

AU - Hildebrandt, Friedhelm

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.

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