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Pediatric Nephrology

, Volume 33, Issue 3, pp 473–483 | Cite as

Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome

  • Guillaume Dorval
  • Olivier Gribouval
  • Vanesa Martinez-Barquero
  • Eduardo Machuca
  • Marie-Josèphe Tête
  • Véronique Baudouin
  • Stéphane Benoit
  • Imen Chabchoub
  • Gérard Champion
  • Dominique Chauveau
  • Hassib Chehade
  • Chokri Chouchane
  • Sylvie Cloarec
  • Pierre Cochat
  • Karin Dahan
  • Jacques Dantal
  • Yahsou Delmas
  • Georges Deschênes
  • Phillippe Dolhem
  • Dominique Durand
  • Zelal Ekinci
  • Khalil El Karoui
  • Michel Fischbach
  • Jean-Pierre Grunfeld
  • Vincent Guigonis
  • Mongia Hachicha
  • Julien Hogan
  • Maryvonne Hourmant
  • Aurélie Hummel
  • Nassim Kamar
  • Thierry Krummel
  • Didier Lacombe
  • Brigitte Llanas
  • Laurent Mesnard
  • Nabil Mohsin
  • Patrick Niaudet
  • Hubert Nivet
  • Paloma Parvex
  • Christine Pietrement
  • Loic de Pontual
  • Claire Pouteil Noble
  • David Ribes
  • Pierre Ronco
  • Eric Rondeau
  • Marion Sallee
  • Michel Tsimaratos
  • Tim Ulinski
  • Rémi Salomon
  • Corinne Antignac
  • Olivia Boyer
Original Article

Abstract

Background

Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease.

Methods

Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort.

Results

Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p < 0.001). Exome sequencing did not reveal any pathogenic mutation, neither did EMP2 sequencing.

Conclusions

Taken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the HLA-DQA1 variation enrichments suggest a complex mode of inheritance.

Keywords

Familial nephrotic syndrome Genetics EMP2 Immunity Steroid sensitivity Steroid resistance Podocyte HLA-DQA1 

Abbreviations

AR

Autosomal recessive

AD

Autosomal dominant

EMP2

Epithelial member protein 2

FR

Frequent relapsers

FSGS

Focal and segmental glomerulosclerosis

OR

Odds ratio

SRNS

Steroid-resistant nephrotic syndrome

SSNS

Steroid-sensitive nephrotic syndrome

WES

Whole exome sequencing

Notes

Acknowledgements

We thank all patients with familial SSNS and their families for their participation in this study. We thank Dr Kalmàn Tory for helpful discussions.

Web resources

The URLs for data presented herein are as follows:

dBSNP: https://www.ncbi.nlm.nih.gov/SNP/

1000genomes project: http://www.internationalgenome.org

PolyPhen: http://genetics.bwh.harvard.edu

SIFT http://sift.jcvi.org

Mutation Taster http://www.mutationtaster.org

ExaC: http://exac.broadinstitute.org

ProteinAtlas: http://www.proteinatlas.org

GeneMatcher: https://genematcher.org

Funding source

Financial support for this work was provided by grants from the European Union’s Seventh Framework Programme (FP7/2007–2013/n°305608-EURenOmics), the “Investments for the Future” program (ANR-10-IAHU-01), and the “Fondation-maladies rares” (FONDATION_HTS-RD – I201309001) to C. Antignac, and The «Fondation pour la Recherche Médicale» (FRM n° DEA20130727711) to G. Dorval.

Compliance with ethical standards

Financial disclosure

The authors have no financial relationships relevant to this article to disclose.

Informed consent

Written informed consent was obtained from participants or their parents, and the study was approved by the Comité de Protection des Personnes “Ile-De-France II.”

Conflicts of interest

The authors have no conflicts of interest relevant to this article to disclose.

Supplementary material

467_2017_3819_MOESM1_ESM.pdf (322 kb)
ESM 1 (PDF 322 kb)
467_2017_3819_MOESM2_ESM.pdf (219 kb)
ESM 2 (PDF 218 kb)
467_2017_3819_MOESM3_ESM.pdf (392 kb)
ESM 3 (PDF 392 kb)
467_2017_3819_MOESM4_ESM.pdf (110 kb)
ESM 4 (PDF 109 kb)

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Copyright information

© IPNA 2017

Authors and Affiliations

  • Guillaume Dorval
    • 1
    • 2
  • Olivier Gribouval
    • 1
    • 2
  • Vanesa Martinez-Barquero
    • 1
    • 2
  • Eduardo Machuca
    • 1
  • Marie-Josèphe Tête
    • 1
    • 2
  • Véronique Baudouin
    • 3
  • Stéphane Benoit
    • 4
  • Imen Chabchoub
    • 5
  • Gérard Champion
    • 6
  • Dominique Chauveau
    • 7
  • Hassib Chehade
    • 8
  • Chokri Chouchane
    • 9
  • Sylvie Cloarec
    • 4
  • Pierre Cochat
    • 10
  • Karin Dahan
    • 11
  • Jacques Dantal
    • 12
  • Yahsou Delmas
    • 13
  • Georges Deschênes
    • 3
  • Phillippe Dolhem
    • 14
  • Dominique Durand
    • 7
  • Zelal Ekinci
    • 15
  • Khalil El Karoui
    • 16
  • Michel Fischbach
    • 17
  • Jean-Pierre Grunfeld
    • 16
  • Vincent Guigonis
    • 18
  • Mongia Hachicha
    • 5
  • Julien Hogan
    • 19
  • Maryvonne Hourmant
    • 12
  • Aurélie Hummel
    • 16
  • Nassim Kamar
    • 7
  • Thierry Krummel
    • 20
  • Didier Lacombe
    • 21
  • Brigitte Llanas
    • 22
  • Laurent Mesnard
    • 23
    • 24
    • 25
  • Nabil Mohsin
    • 26
  • Patrick Niaudet
    • 27
    • 28
  • Hubert Nivet
    • 4
  • Paloma Parvex
    • 29
  • Christine Pietrement
    • 30
    • 31
  • Loic de Pontual
    • 32
  • Claire Pouteil Noble
    • 33
  • David Ribes
    • 7
  • Pierre Ronco
    • 23
    • 24
    • 25
  • Eric Rondeau
    • 23
  • Marion Sallee
    • 34
  • Michel Tsimaratos
    • 35
  • Tim Ulinski
    • 19
  • Rémi Salomon
    • 1
    • 2
    • 27
    • 28
  • Corinne Antignac
    • 1
    • 2
    • 28
    • 36
  • Olivia Boyer
    • 1
    • 2
    • 27
    • 28
  1. 1.INSERM UMR1163, Laboratory of Hereditary Kidney DiseasesImagine InstituteParisFrance
  2. 2.Paris Descartes-Sorbonne Paris Cité University, Imagine InstituteParisFrance
  3. 3.Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de ParisRobert Debré HospitalParisFrance
  4. 4.Department of NephrologyUniversity Hospital of ToursToursFrance
  5. 5.Department of PediatricsSfax UniversitySfaxTunisia
  6. 6.Department of PediatricsUniversity Hospital of AngersAngersFrance
  7. 7.Department of Nephrology and Organ TransplantationUniversity Hospital RangueilToulouseFrance
  8. 8.Department of Pediatrics, Division of Pediatric NephrologyLausanne University HospitalLausanneSwitzerland
  9. 9.Department of PediatricsMonastir UniversityMonastirTunisia
  10. 10.Department of Pediatric NephrologyClaude-Bernard Lyon 1 UniversityBronFrance
  11. 11.Department of Human GeneticsInstitute of Pathology and GeneticsGosseliesBelgium
  12. 12.Nephrology and Immunology DepartmentUniversity Hospital of NantesNantesFrance
  13. 13.Department of NephrologyUniversity Hospital of BordeauxBordeauxFrance
  14. 14.Department of PediatricsSaint-Quentin HospitalSaint-QuentinFrance
  15. 15.Kocaeli Academy for SolidarityKocaeliTurkey
  16. 16.Department of Nephrology, Assistance Publique-Hôpitaux de ParisNecker-Enfants Malades HospitalParisFrance
  17. 17.Nephrology Dialysis Transplantation Children’s UnitUniversity Hospital HautepierreStrasbourgFrance
  18. 18.Department of PediatricsUniversity Hospital of LimogesLimogesFrance
  19. 19.Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de ParisArmand Trousseau HospitalParisFrance
  20. 20.Department of NephrologyUniversity Hospital HautepierreStrasbourgFrance
  21. 21.Department of GeneticsUniversity Hospital of BordeauxBordeauxFrance
  22. 22.Department of PediatricsUniversity Hospital of BordeauxBordeauxFrance
  23. 23.Department of Nephrology and Dialysis, Assistance Publique-Hôpitaux de ParisTenon HospitalParisFrance
  24. 24.Sorbonne University, UPMC University Paris 06ParisFrance
  25. 25.INSERM, UMR_S 1155ParisFrance
  26. 26.College of MedicineSultan Qaboos UniversityMuscatOman
  27. 27.Department of Pediatric Nephrology, Centre de référence du syndrome néphrotique idiopathique de l’enfant et l’adulte, Assistance Publique-Hôpitaux de ParisNecker-Enfants Malades HospitalParisFrance
  28. 28.Centre de Référence Syndrome Néphrotique Idiopathique de l’enfant et de l’adulteParisFrance
  29. 29.Department of Pediatrics, Division of Pediatric NephrologyGeneva University HospitalGenevaSwitzerland
  30. 30.Departement of Pediatrics, Nephrology UnitUniversity Hospital of ReimsReimsFrance
  31. 31.Faculty of Medicine, Laboratory of Biochemistry and Molecular Biology, UMR, CNRS/URCA n°7369University of Champagne-ArdenneReimsFrance
  32. 32.Department of Pediatrics, Assistance Publique-Hôpitaux de ParisJean Verdier HospitalBondyFrance
  33. 33.Department of Nephrology and TransplantationUniversity Hospital of LyonLyonFrance
  34. 34.Department of Nephrology and Kidney TransplantationThe Conception HospitalMarseilleFrance
  35. 35.Department of Multidisciplinary Pediatrics Timone, Assistance Publique Hôpitaux de MarseilleAix-Marseille UniversityMarseilleFrance
  36. 36.Department of Genetics, Assistance Publique-Hôpitaux de ParisNecker-Enfants malades HospitalParisFrance

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