Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management

Bierżyńska, Agnieszka; McCarthy, Hugh; Soderquest, Katrina; Sen, Ethan S; Colby, Elizabeth; Ding, Wen Yi; Nabhan, Marwa M.; Kerecuk, Larissa; Hegde, Shivaram; Hughes, David; Marks, Stephen D.; Feather, Sally; Jones, Caroline; Webb, Nicholas J.A.; Ognjanović, Miloš; Christian, Martin; Gilbert, Rodney D.; Sinha, Manish D.; Lord, Graham M.; Simpson, Michael A.; Koziell, Ania; Welsh, Gavin I.; Saleem, Moin A.

doi:10.1016/j.kint.2016.10.013

Cited by 241 publications

(287 citation statements)

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“…Indeed, mutations have been identified in 75-100% of cases of CNS [8,10,65,66]. Causative mutations appear to largely occur in one of five genes (NPHS1, NPHS2, WT1, LAMB2 and PLCE1).…”

Section: Congenital Nsmentioning

confidence: 99%

“…NPHS1, encoding nephrin, is the main gene implicated in CNS, and mutation is responsible for the autosomal recessive Finnish type (CNF), which typically has a severe phenotype with massive proteinuria and rapid progression to ESRD [11]. However, the NPHS1 mutation detection rate remains high amongst non-Finnish cases of CNS [8,10,65]. Mutations in the NPHS2 gene, encoding podocin, are also responsible for a significant number of CNS cases, and the phenotype varies from the severe CNF presentation to milder disease with onset of proteinuria occurring later than in those with NPHS1 mutations [4,66,67].…”

Section: Congenital Nsmentioning

confidence: 99%

“…Monogenic NS, which presents in infancy (from 4 to 12 months of life) and during childhood, is most commonly attributed to mutations in the NPHS2 gene, encoding podocin [8,68]. There is a recognised genotype to phenotype correlation that explains this phenotypic variability [12,66,69].…”

Section: Infantile and Childhood Nsmentioning

confidence: 99%

“…There is a recognised genotype to phenotype correlation that explains this phenotypic variability [12,66,69]. Recent whole-exome sequencing performed on a paediatric cohort of SRNS patients revealed the mean age of onset associated with NPHS2 mutations to be approximately 6 years [8]. That said, it is clearly important to consider NPHS2 mutation as a cause for SRNS in a child of any age and, conversely, to expect a low rate of NPHS2 mutations in certain ethnic groups, namely Chinese, Japanese and Korean [10,70].…”

Section: Infantile and Childhood Nsmentioning

confidence: 99%

“…Mutations in WT1 cause isolated and syndromic SRNS, which will be discussed later in this review. Previous studies have estimated WT1 mutations to account for approximately 6% of sporadic SRNS cases in childhood, manifesting at any age, depending on the underlying mutation [8,66,75,76]. Genotype-phenotype correlations have been drawn from specific WT1 mutations.…”

Section: Infantile and Childhood Nsmentioning

confidence: 99%

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Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

2017

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Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in childhood and has a significant risk of rapid progression to end-stage renal disease. The identification of over 50 monogenic causes of SRNS has revealed dysfunction in podocyte-associated proteins in the pathogenesis of proteinuria, highlighting their essential role in glomerular function. Recent technological advances in high-throughput sequencing have enabled indication-driven genetic panel testing for patients with SRNS. The availability of genetic testing, combined with the significant phenotypic variability of monogenic SRNS, poses unique challenges for clinicians when directing genetic testing. This highlights the need for clear clinical guidelines that provide a systematic approach for mutational screening in SRNS. The likelihood of identifying a causative mutation is inversely related to age at disease onset and is increased with a positive family history or the presence of extra-renal manifestations. An unequivocal molecular diagnosis could allow for a personalised treatment approach with weaning of immunosuppressive therapy, avoidance of renal biopsy and provision of accurate, well-informed genetic counselling. Identification of novel causative mutations will continue to unravel the pathogenic mechanisms of glomerular disease and provide new insights into podocyte biology and glomerular function.

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“…Indeed, mutations have been identified in 75-100% of cases of CNS [8,10,65,66]. Causative mutations appear to largely occur in one of five genes (NPHS1, NPHS2, WT1, LAMB2 and PLCE1).…”

Section: Congenital Nsmentioning

confidence: 99%

Section: Congenital Nsmentioning

confidence: 99%

Section: Infantile and Childhood Nsmentioning

confidence: 99%

Section: Infantile and Childhood Nsmentioning

confidence: 99%

Section: Infantile and Childhood Nsmentioning

confidence: 99%

See 3 more Smart Citations

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

2017

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Common Threads in Pediatric Inflammatory Diseases

2018

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Pediatric inflammatory diseases include a spectrum of complex interactions among host genomics, immune response, and environmental exposures. Despite this common thread, alterations in these interactions lead to different disease phenotypes and are often approached by each subspecialty in isolation. In actuality, these different diseases often share causative pathways and subsequently may have common therapeutic targets. Indeed, in this era of precision medicine, integration of the expertise among different disciplines will allow us to identify therapies that are more precise and effective. By learning from one another's successes and failures, we can develop a personalized approach to each patient, guided by the phenotype and disease severity.In this issue of JAMA Pediatrics, Basu et al 1 demonstrate a targeted approach through use of rituximab as primary therapy in patients with severe nephrotic disease. Nephrotic syndrome is the most common pediatric primary glomerular disease, and most children respond favorably to corticosteroids. [2][3][4] Unfortunately, some children develop corticosteroid-dependent nephrotic syndrome that is often refractory to medications. Up to 50% of these children progress to end-stage renal disease within 10 years. 5 Histologic features frequently seen in kidney biopsies of patients with corticosteroid-resistant nephrotic syndrome are consistent with focal segmental glomerulosclerosis. The presence of focal segmental glomerulosclerosis is associated with a 33% risk recurrence of nephrotic syndrome rapidly after kidney transplant, indicating that this disease is not inherent to the native kidney alone, but also has circulating factors.The etiologic hypotheses of nephrotic syndrome have evolved from a primary T-cell dysfunction to T-regulatory cell dysfunction, and currently are thought to involve B-cellderived factors. The developing insight into the disease mechanism has led to changes in therapy. Tacrolimus, a calcineurin inhibitor, which is the initial therapeutic approach following corticosteroid failure, primarily functions through inhibiting interleukin 2 production and T-lymphocyte activation. Tacrolimus also affects broader cytokine production in addition to interleukin 2, as well as growth and differentiation of B lymphocytes. 6,7 Rituximab is an anti-CD20 antibody that depletes B cells. More children with refractory nephrotic syndrome had longer disease-free response to rituximab compared with tacrolimus in this study, which may point to improved targeting of the mechanism of disease.

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