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Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management
被引:212
|作者:
Bierzynska, Agnieszka
[1
]
McCarthy, Hugh J.
[1
]
Soderquest, Katrina
[2
]
Sen, Ethan S.
[1
]
Colby, Elizabeth
[1
]
Ding, Wen Y.
[1
]
Nabhan, Marwa M.
[3
]
Kerecuk, Larissa
[4
]
Hegde, Shivram
[5
]
Hughes, David
[6
]
Marks, Stephen
[7
]
Feather, Sally
[8
]
Jones, Caroline
[9
]
Webb, Nicholas J. A.
[10
,11
]
Ognjanovic, Milos
[12
]
Christian, Martin
[13
]
Gilbert, Rodney D.
[14
,15
]
Sinha, Manish D.
[16
]
Lord, Graham M.
Simpson, Michael
[17
]
Koziell, Ania B.
[2
]
Welsh, Gavin I.
[1
]
Saleem, Moin A.
[1
]
机构:
[1] Univ Bristol, Sch Clin Sci, Bristol Renal & Childrens Renal Unit, Bristol BS8 1TH, Avon, England
[2] Kings Coll London, Fac Life Sci & Med, Dept Expt lmmunobiol, Div Transplantat Immunol & Mucosal Biol, London, England
[3] Cairo Univ, Kasr Al Ainy Sch Med, Dept Paediat, EGORD, Cairo, Egypt
[4] Birmingham Childrens Hosp, Birmingham, W Midlands, England
[5] Univ Hosp Wales, Cardiff, S Glam, Wales
[6] Royal Hosp Children, Glasgow, Lanark, Scotland
[7] Great Ormond St Hosp Sick Children, London, England
[8] St James Univ Hosp, Leeds, W Yorkshire, England
[9] Alder Hey Childrens Hosp, Liverpool, Merseyside, England
[10] Univ Manchester, Manchester Acad Hlth Sci Ctr, Royal Manchester Childrens Hosp, Dept Paediat Nephrol, Manchester, Lancs, England
[11] Univ Manchester, Manchester Acad Hlth Sci Ctr, Royal Manchester Childrens Hosp, NIHR Wellcome Trust Clin Res Facil, Manchester, Lancs, England
[12] Newcastle upon Tyne Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
[13] QMC, Nottingham Childrens Hosp, Nottingham, England
[14] Southampton Childrens Hosp, Southampton, Hants, England
[15] Univ Southampton, Sch Med, Southampton, Hants, England
[16] Guys & St Thomas Hosp, London, England
[17] Kings Coll London, Fac Life Sci & Med, Div Genet & Mol Med, London, England
关键词:
cytoskeleton;
focal segmental glomerulosclerosis;
nephrotic syndrome;
pediatric nephrology;
podocyte;
proteinuria;
STEROID-RESISTANT;
NPHS2;
MUTATIONS;
CHILDREN;
NEPHROPATHY;
D O I:
10.1016/j.kint.2016.10.013
中图分类号:
R5 [内科学];
R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号:
1002 ;
100201 ;
摘要:
Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9-30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and nonmonogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence -based algorithm for clinical management.
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页码:937 / 947
页数:11
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