Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity

Daniela A. Braun, Markus Schueler, Jan Halbritter, Heon Yung Gee, Jonathan D. Porath, Jennifer A. Lawson, Rannar Airik, Shirlee Shril, Susan J. Allen, Deborah Stein, Adila Al Kindy, Bodo B. Beck, Nurcan Cengiz, Khemchand N. Moorani, Fatih Ozaltin, Seema Hashmi, John A. Sayer, Detlef Bockenhauer, Neveen A. Soliman, Edgar A. OttoRichard P. Lifton, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering and identified 5 novel candidate genes (RBM48, FAM186B, PIAS1, INCENP, and RCOR1) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis, and allows identification of novel candidate genes.

Original languageEnglish
Pages (from-to)468-475
Number of pages8
JournalKidney International
Volume89
Issue number2
DOIs
Publication statusPublished - 2016 Feb 1

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Exome
Chronic Renal Insufficiency
Kidney
Mutation
Autosomal Recessive Polycystic Kidney
Autoimmune Polyendocrinopathies
Hereditary Nephritis
Genes
Autosomal Dominant Polycystic Kidney
Genetic Association Studies
Ciliopathies

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Braun, Daniela A. ; Schueler, Markus ; Halbritter, Jan ; Gee, Heon Yung ; Porath, Jonathan D. ; Lawson, Jennifer A. ; Airik, Rannar ; Shril, Shirlee ; Allen, Susan J. ; Stein, Deborah ; Al Kindy, Adila ; Beck, Bodo B. ; Cengiz, Nurcan ; Moorani, Khemchand N. ; Ozaltin, Fatih ; Hashmi, Seema ; Sayer, John A. ; Bockenhauer, Detlef ; Soliman, Neveen A. ; Otto, Edgar A. ; Lifton, Richard P. ; Hildebrandt, Friedhelm. / Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity. In: Kidney International. 2016 ; Vol. 89, No. 2. pp. 468-475.
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abstract = "Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering and identified 5 novel candidate genes (RBM48, FAM186B, PIAS1, INCENP, and RCOR1) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis, and allows identification of novel candidate genes.",
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Braun, DA, Schueler, M, Halbritter, J, Gee, HY, Porath, JD, Lawson, JA, Airik, R, Shril, S, Allen, SJ, Stein, D, Al Kindy, A, Beck, BB, Cengiz, N, Moorani, KN, Ozaltin, F, Hashmi, S, Sayer, JA, Bockenhauer, D, Soliman, NA, Otto, EA, Lifton, RP & Hildebrandt, F 2016, 'Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity', Kidney International, vol. 89, no. 2, pp. 468-475. https://doi.org/10.1038/ki.2015.317

Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity. / Braun, Daniela A.; Schueler, Markus; Halbritter, Jan; Gee, Heon Yung; Porath, Jonathan D.; Lawson, Jennifer A.; Airik, Rannar; Shril, Shirlee; Allen, Susan J.; Stein, Deborah; Al Kindy, Adila; Beck, Bodo B.; Cengiz, Nurcan; Moorani, Khemchand N.; Ozaltin, Fatih; Hashmi, Seema; Sayer, John A.; Bockenhauer, Detlef; Soliman, Neveen A.; Otto, Edgar A.; Lifton, Richard P.; Hildebrandt, Friedhelm.

In: Kidney International, Vol. 89, No. 2, 01.02.2016, p. 468-475.

Research output: Contribution to journalArticle

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T1 - Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity

AU - Braun, Daniela A.

AU - Schueler, Markus

AU - Halbritter, Jan

AU - Gee, Heon Yung

AU - Porath, Jonathan D.

AU - Lawson, Jennifer A.

AU - Airik, Rannar

AU - Shril, Shirlee

AU - Allen, Susan J.

AU - Stein, Deborah

AU - Al Kindy, Adila

AU - Beck, Bodo B.

AU - Cengiz, Nurcan

AU - Moorani, Khemchand N.

AU - Ozaltin, Fatih

AU - Hashmi, Seema

AU - Sayer, John A.

AU - Bockenhauer, Detlef

AU - Soliman, Neveen A.

AU - Otto, Edgar A.

AU - Lifton, Richard P.

AU - Hildebrandt, Friedhelm

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering and identified 5 novel candidate genes (RBM48, FAM186B, PIAS1, INCENP, and RCOR1) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis, and allows identification of novel candidate genes.

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