Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children.
Adolescent
Atypical Hemolytic Uremic Syndrome
/ diagnosis
Child
Child, Preschool
Cohort Studies
DNA Mutational Analysis
Diagnosis, Differential
Female
Genetic Markers
Humans
Infant
Infant, Newborn
Male
Mutation
Nephritis
/ diagnosis
Nephritis, Hereditary
/ diagnosis
Nephrosis
/ diagnosis
Nephrotic Syndrome
/ diagnosis
Prognosis
Exome Sequencing
/ methods
genetics
monogenic renal disease
nephritis, nephrotic syndrome
pediatrics
Journal
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
ISSN: 1460-2385
Titre abrégé: Nephrol Dial Transplant
Pays: England
ID NLM: 8706402
Informations de publication
Date de publication:
01 03 2019
01 03 2019
Historique:
received:
12
09
2017
accepted:
21
01
2018
pubmed:
9
10
2018
medline:
28
12
2019
entrez:
9
10
2018
Statut:
ppublish
Résumé
Alport syndrome (AS) and atypical hemolytic-uremic syndrome (aHUS) are rare forms of chronic kidney disease (CKD) that can lead to a severe decline of renal function. Steroid-resistant nephrotic syndrome (SRNS) is more common than AS and aHUS and causes 10% of childhood-onset CKD. In recent years, multiple monogenic causes of AS, aHUS and SRNS have been identified, but their relative prevalence has yet to be studied together in a typical pediatric cohort of children with proteinuria and hematuria. We hypothesized that identification of causative mutations by whole exome sequencing (WES) in known monogenic nephritis and nephrosis genes would allow distinguishing nephritis from nephrosis in a typical pediatric group of patients with both proteinuria and hematuria at any level. We therefore conducted an exon sequencing (WES) analysis for 11 AS, aHUS and thrombotic thrombocytopenic purpura-causing genes in an international cohort of 371 patients from 362 families presenting with both proteinuria and hematuria before age 25 years. In parallel, we conducted either WES or high-throughput exon sequencing for 23 SRNS-causing genes in all patients. We detected pathogenic mutations in 18 of the 34 genes analyzed, leading to a molecular diagnosis in 14.1% of families (51 of 362). Disease-causing mutations were detected in 3 AS-causing genes (4.7%), 3 aHUS-causing genes (1.4%) and 12 NS-causing genes (8.0%). We observed a much higher mutation detection rate for monogenic forms of CKD in consanguineous families (35.7% versus 10.1%). We present the first estimate of relative frequency of inherited AS, aHUS and NS in a typical pediatric cohort with proteinuria and hematuria. Important therapeutic and preventative measures may result from mutational analysis in individuals with proteinuria and hematuria.
Sections du résumé
BACKGROUND
Alport syndrome (AS) and atypical hemolytic-uremic syndrome (aHUS) are rare forms of chronic kidney disease (CKD) that can lead to a severe decline of renal function. Steroid-resistant nephrotic syndrome (SRNS) is more common than AS and aHUS and causes 10% of childhood-onset CKD. In recent years, multiple monogenic causes of AS, aHUS and SRNS have been identified, but their relative prevalence has yet to be studied together in a typical pediatric cohort of children with proteinuria and hematuria. We hypothesized that identification of causative mutations by whole exome sequencing (WES) in known monogenic nephritis and nephrosis genes would allow distinguishing nephritis from nephrosis in a typical pediatric group of patients with both proteinuria and hematuria at any level.
METHODS
We therefore conducted an exon sequencing (WES) analysis for 11 AS, aHUS and thrombotic thrombocytopenic purpura-causing genes in an international cohort of 371 patients from 362 families presenting with both proteinuria and hematuria before age 25 years. In parallel, we conducted either WES or high-throughput exon sequencing for 23 SRNS-causing genes in all patients.
RESULTS
We detected pathogenic mutations in 18 of the 34 genes analyzed, leading to a molecular diagnosis in 14.1% of families (51 of 362). Disease-causing mutations were detected in 3 AS-causing genes (4.7%), 3 aHUS-causing genes (1.4%) and 12 NS-causing genes (8.0%). We observed a much higher mutation detection rate for monogenic forms of CKD in consanguineous families (35.7% versus 10.1%).
CONCLUSIONS
We present the first estimate of relative frequency of inherited AS, aHUS and NS in a typical pediatric cohort with proteinuria and hematuria. Important therapeutic and preventative measures may result from mutational analysis in individuals with proteinuria and hematuria.
Identifiants
pubmed: 30295827
pii: 4950571
doi: 10.1093/ndt/gfy050
pmc: PMC6399484
doi:
Substances chimiques
Genetic Markers
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
474-485Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK076683
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007726
Pays : United States
Informations de copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
Références
Nat Genet. 1994 Sep;8(1):77-81
pubmed: 7987396
J Med Genet. 2003 Sep;40(9):676-81
pubmed: 12960213
Ren Fail. 2015;37(8):1329-37
pubmed: 26211502
Nat Methods. 2014 Apr;11(4):361-2
pubmed: 24681721
Am J Hum Genet. 1998 Apr;62(4):824-33
pubmed: 9529364
J Med Genet. 2004 Jun;41(6):e84
pubmed: 15173250
Nat Rev Nephrol. 2016 Mar;12(3):133-46
pubmed: 26750453
J Clin Invest. 2013 Dec;123(12):5179-89
pubmed: 24270420
Nat Genet. 1998 May;19(1):47-50
pubmed: 9590287
Pediatr Nephrol. 2016 Jun;31(6):941-55
pubmed: 26809805
Acta Medica (Hradec Kralove). 2010;53(3):157-9
pubmed: 21171529
J Am Soc Nephrol. 2002 Feb;13(2):388-93
pubmed: 11805166
Nat Genet. 2000 May;25(1):125
pubmed: 10802674
J Med Genet. 2015 Mar;52(3):163-74
pubmed: 25575550
Am J Ophthalmol. 2008 Oct;146(4):602-611
pubmed: 18672223
Hum Mutat. 2010 Nov;31(11):1179-84
pubmed: 20683926
Am J Hum Genet. 2015 Jan 8;96(1):153-61
pubmed: 25557779
PLoS One. 2013 Oct 10;8(10):e76360
pubmed: 24130771
Arch Dis Child. 1978 Mar;53(3):255-6
pubmed: 646435
Nat Genet. 2013 May;45(5):531-6
pubmed: 23542698
Nat Genet. 2010 Jan;42(1):72-6
pubmed: 20023659
Am J Kidney Dis. 2012 Jul;60(1):121-5
pubmed: 22503529
Am J Hum Genet. 2000 Jun;66(6):1945-57
pubmed: 10796874
J Am Soc Nephrol. 2001 Dec;12(12):2742-6
pubmed: 11729243
Am J Med Genet A. 2005 Jun 1;135(2):202-5
pubmed: 15880370
Am J Hum Genet. 2006 Dec;79(6):1125-9
pubmed: 17186472
J Am Soc Nephrol. 2007 Oct;18(10):2773-80
pubmed: 17855635
Science. 2005 Jun 17;308(5729):1801-4
pubmed: 15879175
Clin Genet. 2015 Nov;88(5):456-61
pubmed: 25307543
Nat Genet. 2000 Mar;24(3):251-6
pubmed: 10700177
Hum Mol Genet. 1994 Aug;3(8):1269-73
pubmed: 7987301
Pediatr Nephrol. 2004 Dec;19(12):1340-8
pubmed: 15338398
Nephrol Dial Transplant. 2008 Nov;23(11):3527-33
pubmed: 18503012
J Clin Invest. 2013 Aug;123(8):3243-53
pubmed: 23867502
Gene. 2017 Aug 20;625:15-20
pubmed: 28476686
Nephrol Dial Transplant. 2016 Nov;31(11):1802-1813
pubmed: 26507970
Kidney Int. 2014 May;85(5):1208-13
pubmed: 24304881
Clin J Am Soc Nephrol. 2010 Oct;5(10):1844-59
pubmed: 20595690
Nat Rev Nephrol. 2013 Mar;9(3):170-8
pubmed: 23165304
PLoS Genet. 2009 Jan;5(1):e1000353
pubmed: 19165332
J Clin Invest. 2011 Oct;121(10):4127-37
pubmed: 21911940
Kidney Int. 2007 Nov;72(10):1198-203
pubmed: 17713465
Pediatr Transplant. 2007 Jun;11(4):366-73
pubmed: 17493215
Lancet. 2003 Nov 8;362(9395):1542-7
pubmed: 14615110
J Am Soc Nephrol. 2015 Jun;26(6):1279-89
pubmed: 25349199
Nature. 2012 Jan 22;482(7383):98-102
pubmed: 22266938
Nat Genet. 2002 Feb;30(2):215-20
pubmed: 11799392
Pediatr Nephrol. 2017 Jul;32(7):1181-1192
pubmed: 28204945
Pediatr Nephrol. 2015 Sep;30(9):1477-83
pubmed: 25903641
Nat Genet. 2000 Apr;24(4):349-54
pubmed: 10742096
J Clin Invest. 2011 May;121(5):2013-24
pubmed: 21540551
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):240-5
pubmed: 17182750
N Engl J Med. 2012 Apr 19;366(16):1508-14
pubmed: 22512483
N Engl J Med. 2011 Jul 28;365(4):295-306
pubmed: 21756023
Nephrol Ther. 2013 Dec;9(7):494-6
pubmed: 23932794
J Am Soc Nephrol. 2014 Feb;25(2):260-75
pubmed: 24262798
J Am Soc Nephrol. 2011 Oct;22(10):1815-20
pubmed: 21903995
Am J Hum Genet. 1996 Jun;58(6):1347-63
pubmed: 8651312
Mol Cell. 1998 Mar;1(4):575-82
pubmed: 9660941
J Med Genet. 2013 May;50(5):330-8
pubmed: 23434736
Nephrol Dial Transplant. 2014 Jan;29(1):81-8
pubmed: 24042019
Nat Genet. 2000 May;25(1):12-3
pubmed: 10802644
Blood. 2006 Aug 15;108(4):1267-79
pubmed: 16621965
Genet Mol Res. 2015 Jan 23;14(1):433-9
pubmed: 25729976
Hum Pathol. 2014 Nov;45(11):2326-33
pubmed: 25260719
J Am Soc Nephrol. 2013 Feb;24(3):364-75
pubmed: 23349312
Nephron Clin Pract. 2011;118(1):c9-c18
pubmed: 21071975
Hum Mutat. 1999;13(2):124-32
pubmed: 10094548
Nature. 2001 Oct 4;413(6855):488-94
pubmed: 11586351
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Nephrol Dial Transplant. 2016 Jun;31(6):961-70
pubmed: 26346198
J Hum Genet. 2012 Jul;57(7):459-64
pubmed: 22622361
Blood. 2008 Dec 15;112(13):4948-52
pubmed: 18796626
PLoS Genet. 2007 Mar 16;3(3):e41
pubmed: 17367211
Am J Hum Genet. 2011 Jul 15;89(1):139-47
pubmed: 21722858
J Med Genet. 2012 Dec;49(12):756-67
pubmed: 23188109
Orphanet J Rare Dis. 2012 Aug 28;7:56
pubmed: 22929189
Nat Genet. 2014 Mar;46(3):299-304
pubmed: 24509478
Nephrol Dial Transplant. 2010 Sep;25(9):2970-6
pubmed: 20172850
Lancet. 2010 Sep 4;376(9743):794-801
pubmed: 20800271
Am J Kidney Dis. 2000 Jul;36(1):190-6
pubmed: 10873890
Nat Genet. 2006 Dec;38(12):1397-405
pubmed: 17086182
J Am Soc Nephrol. 2014 Dec;25(12):2740-51
pubmed: 24854265
Pediatr Nephrol. 2012 Aug;27(8):1283-91
pubmed: 22410797
Nat Genet. 2006 Jun;38(6):674-81
pubmed: 16682973
J Clin Invest. 1994 Mar;93(3):1195-207
pubmed: 8132760
Hum Mutat. 2014 Feb;35(2):178-86
pubmed: 24227627
Hum Mol Genet. 2004 Nov 1;13(21):2625-32
pubmed: 15367484
J Am Soc Nephrol. 2015 Jan;26(1):230-6
pubmed: 25060053
Invest Ophthalmol Vis Sci. 2014 Jun 06;55(7):4455-60
pubmed: 24906858
N Engl J Med. 2009 Jul 23;361(4):345-57
pubmed: 19625716
Nephron Clin Pract. 2012;120(3):c139-46
pubmed: 22584503
Nat Protoc. 2009;4(7):1073-81
pubmed: 19561590