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A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome

Carolin E. Sadowski, Svjetlana Lovric, Shazia Ashraf, Werner L. Pabst, Heon Yung Gee, Stefan Kohl, Susanne Engelmann, Virginia Vega-Warner, Humphrey Fang, Jan Halbritter, Michael J. Somers, Weizhen Tan, Shirlee Shril, Inès Fessi, Richard P. Lifton, Detlef Bockenhauer, Sherif El-Desoky, Jameela A. Kari, Martin Zenker, Markus J. Kemper, Dominik Mueller, Hanan M. Fathy, Neveen A. Soliman, the SRNS Study Group and Friedhelm Hildebrandt
JASN June 2015, 26 (6) 1279-1289; DOI: https://doi.org/10.1681/ASN.2014050489
Carolin E. Sadowski
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Svjetlana Lovric
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Shazia Ashraf
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Werner L. Pabst
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Heon Yung Gee
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Stefan Kohl
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Susanne Engelmann
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Virginia Vega-Warner
†Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan;
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Humphrey Fang
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Jan Halbritter
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Michael J. Somers
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Weizhen Tan
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Shirlee Shril
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Inès Fessi
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
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Richard P. Lifton
‡Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut;
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Detlef Bockenhauer
§Institute of Child Health, University College London, London, United Kingdom;
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Sherif El-Desoky
‖Pediatric Nephrology Unit, King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia;
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Jameela A. Kari
‖Pediatric Nephrology Unit, King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia;
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Martin Zenker
¶Department of Human Genetics, Otto von Guericke University, Magdeburg, Germany;
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Markus J. Kemper
**Department of Pediatrics, University Hospital Hamburg-Eppendorf, Hamburg, Germany;
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Dominik Mueller
††Department of Pediatric Nephrology, Medical Faculty of the Charité, Berlin, Germany;
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Hanan M. Fathy
‡‡The Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt;
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Neveen A. Soliman
§§Department of Pediatrics, Center of Pediatric Nephrology & Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt;
‖‖Egyptian Group for Orphan Renal Diseases, Cairo, Egypt; and
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Friedhelm Hildebrandt
*Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
¶¶Howard Hughes Medical Institute, Chevy Chase, Maryland
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    Figure 1.

    Geographic distribution of the study cohort of 1783 families with SRNS. The number of affected families in the respective countries or cities is represented by the surface area (red) of a circle. Data from countries not represented on the map are shown in the blue box. Insert shows higher resolution of the New York Metropolitan area.

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    Figure 2.

    Age of onset distribution (in years) for 1589 of 1783 examined SRNS families. The displayed 1589 families represent the number of families with available data for age of onset of proteinuria <18 years. (A) Red curve and histograms represent the number of families in each age of onset (years) of SRNS for 1093 families without molecular genetic diagnosis. Blue curve and histograms show number of 496 families with causative mutations identified for each age of onset. (B) Graph indicates percentage of solved families per year of age of onset (from A). Black dotted line represents a binomial fit of age-related percent of families with causative mutation. (Data are not displayed for 72 individuals who were older than 17 years at onset of SRNS and for 122 families with no available information for age of onset. In families with >1 affected family member, the mean age of onset from all affected individuals was used.)

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    Figure 3.

    Detection of the causative mutation in 502 families in an international cohort of 1617 families with SRNS in 21 SRNS-causing genes in relation to age of onset of proteinuria in clinically relevant age groups. The displayed 502 families represent the number of families with detected causative mutation and available data for age of onset of proteinuria <26 years. (A) Percentage of families with causative mutation detected per gene per age group. Histograms indicate fraction (in percentage) of families with causative gene detected in n families per families examined (on top of histograms) per age group. (B) Percentages shown in A are represented by separate bars to highlight distribution across age groups as further delineated in C. Note that mutations in NPHS1 or LAMB2 cause early-onset SRNS, whereas mutations in INF2 or TRPC6 cause late-onset SRNS. (C) Percentages of families with causative mutation detected (from B) are interconnected by lines between age groups and shown in different colors for each causative gene (lower panel for recessive genes, upper panel for dominant genes). NPHS1 mutations (red) have an early age of onset and are rarely found in patients older than 6 years. The dominant genes INF2 and TRPC6 manifest in early adulthood and WT1 (black) shows a biphasic distribution (upper panel). (For families with detected disease-causing mutation, data are not shown for 11 families where no age of onset was available, and for 10 families with an age of onset older than 25 years. For families with no detection of the disease-causing mutation, data are not displayed for 111 families for whom no data for age of onset were available and for 34 families with age of onset older than 25 years. In families with >1 affected family member the mean age of onset from all affected individuals was calculated.).

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    Figure 4.

    Distribution for age of onset of NS in 35 individuals with homozygous mutations in PLCE1. (A) Homozygous PLCE1 mutations are represented by 30 different alleles. The x-axis indicates the mutations sorted by median age of onset. The y-axis indicates the age of onset of SRNS. Symbols are colored red, green, or blue if the allele is truncating, splice, or missense, respectively. (B) Age of onset of SRNS with causative mutations detected in PLCE1, grouped by type of mutation. The x-axis indicates the type of mutations (truncating mutations before amino acid (aa) residue 1000 (N-terminal), truncating mutations after aa residue 1000 (C-terminal), splice and missense mutations. The y-axis indicates the age of onset of proteinuria. Symbols are blue for missense, green for splice, and red for stop and frameshift. Note that the age of onset was significantly different between splice site mutations versus C-terminal truncating mutations (P<0.05), or splice site versus missense mutations (P<0.05). P values are from two-tailed t test. Arrows represent position of outlier values.

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    Table 1.

    International cohort of 526 of the 1783 families, in whom a single-gene cause of SRNS was detected in 1 of 21 monogenic causes of SRNS (27 genes examined)

    Gene Causing SRNSMode of InheritanceSRNS Families Molecularly Diagnosed by Sanger Sequencing (Published Previously), naSRNS Families Molecularly Diagnosed by Multiplex PCR (n)Total SRNS Families with Molecular Diagnosis (% of Families)
    NPHS2AR170 (42)7177 (9.93)
    NPHS1AR93 (61)38131 (7.34)
    WT1AD78 (50)785 (4.77)
    PLCE1AR23 (16)1437 (2.17)
    LAMB2AR10 (6)1020 (1.12)
    SMARCAL1AR1 (0)1516 (0.89)
    INF2AD2 (0)79 (0.5)
    TRPC6AD1 (1)89 (0.53)
    COQ6AR6 (5)28 (0.45)
    ITGA3AR3 (3)25 (0.28)
    MYO1EAR0 (0)55 (0.28)
    CUBNAR1 (1)45 (0.28)
    COQ2AR0 (0)44 (0.22)
    LMX1BAD0 (0)44 (0.22)
    ADCK4AR3 (3)03 (0.17)
    DGKE1AR0 (0)22 (0.11)
    PDSS2AR0 (0)22 (0.11)
    ARHGAP24AD0 (0)11 (0.06)
    ARHGDIAAR1 (1)01 (0.06)
    CFHAR0 (0)11 (0.06)
    ITGB4AR0 (0)11 (0.06)
     Total392 (189)134526 (29.5)
    • AD, autosomal dominant; AR, autosomal recessive.

    • ↵a Number in parenthesis show “molecularly solved” families with causative mutation detected that were published before from our cohort (see literature).

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Journal of the American Society of Nephrology: 26 (6)
Journal of the American Society of Nephrology
Vol. 26, Issue 6
June 2015
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A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome
Carolin E. Sadowski, Svjetlana Lovric, Shazia Ashraf, Werner L. Pabst, Heon Yung Gee, Stefan Kohl, Susanne Engelmann, Virginia Vega-Warner, Humphrey Fang, Jan Halbritter, Michael J. Somers, Weizhen Tan, Shirlee Shril, Inès Fessi, Richard P. Lifton, Detlef Bockenhauer, Sherif El-Desoky, Jameela A. Kari, Martin Zenker, Markus J. Kemper, Dominik Mueller, Hanan M. Fathy, Neveen A. Soliman, the SRNS Study Group, Friedhelm Hildebrandt
JASN Jun 2015, 26 (6) 1279-1289; DOI: 10.1681/ASN.2014050489

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A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome
Carolin E. Sadowski, Svjetlana Lovric, Shazia Ashraf, Werner L. Pabst, Heon Yung Gee, Stefan Kohl, Susanne Engelmann, Virginia Vega-Warner, Humphrey Fang, Jan Halbritter, Michael J. Somers, Weizhen Tan, Shirlee Shril, Inès Fessi, Richard P. Lifton, Detlef Bockenhauer, Sherif El-Desoky, Jameela A. Kari, Martin Zenker, Markus J. Kemper, Dominik Mueller, Hanan M. Fathy, Neveen A. Soliman, the SRNS Study Group, Friedhelm Hildebrandt
JASN Jun 2015, 26 (6) 1279-1289; DOI: 10.1681/ASN.2014050489
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