Mutation Analysis of &lt;b&gt;&lt;i&gt;NPHS1 &lt;/i&gt;&lt;/b&gt;in a Worldwide Cohort of Congenital Nephrotic Syndrome Patients

Övünç, Buğsu; Ashraf, Shazia; Vega-Warner, Virginia; Böckenhauer, Detlef; Soliman, Neveen A.; Joseph, Mark; Hildebrandt, Friedhelm

doi:10.1159/000337379

Cited by 33 publications

(21 citation statements)

References 86 publications

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“…Although variable expressivity of the SRNS phenotype in patients with monogenic NS has certainly been reported, 4,29,[54][55][56][57] the immunosuppressive-resistant phenotype in monogenic NS has been of greater focus. 2,5,21,22,25,[58][59][60] Arguably, the strongest motivation for clinicians and families to perform genetic screening is the belief that this diagnosis would allow avoidance of immunosuppressant agents that would only harm with no chance of benefit.…”

Section: Discussionmentioning

confidence: 99%

Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort

Sampson

Gillies

Robertson

et al. 2015

JASN

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To maximize clinical benefits of genetic screening of patients with nephrotic syndrome (NS) to diagnose monogenic causes, reliably distinguishing NS-causing variants from the background of rare, noncausal variants prevalent in all genomes is vital. To determine the prevalence of monogenic NS in a North American case cohort while accounting for background prevalence of genetic variation, we sequenced 21 implicated monogenic NS genes in 312 participants from the Nephrotic Syndrome Study Network and 61 putative controls from the 1000 Genomes Project (1000G). These analyses were extended to available sequence data from approximately 2500 subjects from the 1000G. A typical pathogenicity filter identified causal variants for NS in 4.2% of patients and 5.8% of subjects from the 1000G. We devised a more stringent pathogenicity filtering strategy, reducing background prevalence of causal variants to 1.5%. When applying this stringent filter to patients, prevalence of monogenic NS was 2.9%; of these patients, 67% were pediatric, and 44% had FSGS on biopsy. The rate of complete remission did not associate with monogenic classification. Thus, we identified factors contributing to inaccurate monogenic classification of NS and developed a more accurate variant filtering strategy. The prevalence and clinical correlates of monogenic NS in this sporadically affected cohort differ substantially from those reported for patients referred for genetic analysis. Particularly in unselected, population-based cases, considering putative causal variants in known NS genes from a probabilistic rather than a deterministic perspective may be more precise. We also introduce GeneVetter, a web tool for monogenic assessment of rare disease.

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Section: Discussionmentioning

confidence: 99%

Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort

Sampson

Gillies

Robertson

et al. 2015

JASN

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“…5,9,11,32-37 253 families of these 1783 families, with age of onset ,1 year (congenital nephrotic syndrome), were additionally sequenced for mutations in NPHS1. 9,32,[38][39][40][41] In August 2013, when 27 single-gene causes of SRNS were published, the same 1783 families with SRNS were examined for these 27 reported SRNS genes (Supplemental Table 2). We therefore used a strategy of microfluidic multiplex PCR and next-generation sequencing that we recently developed.…”

Section: Study Participantsmentioning

confidence: 99%

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

Sadowski

Lovric

Ashraf

et al. 2015

Journal of the American Society of Nephrology

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557

642

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Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q 10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available.

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“…Mutations of the NPHS1 gene that encodes nephrin on the chromosome 19q13.1 has been found to be responsible for an autosomal recessive form of congenital nephrosis syndrome also termed as Finnish nephropathy (13,29,56,63). In addition, mutations in the gene NPHS2 (podocin) have been associated with steroid-resistant idiopathic nephrosis syndrome.…”

Section: Focal Segmental Glomerulosclerosismentioning

confidence: 99%

Regulation of TRPC6 ion channels in podocytes — Implications for focal segmental glomerulosclerosis and acquired forms of proteinuric diseases

Szabó¹,

Ambrus²,

Zákány³

et al. 2015

Acta Physiologica Hungarica

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The glomerular filtration barrier is a highly specialized tri-layer structure with unique functional properties. Podocyte dysfunction and cytoskeletal disorganization leads to disruption of the slit diaphragma, and proteinuria. Inflammatory diseases involving the kidney as well as inherited podocytopathies or diabetic nephropathy cause injury of the podocyte network. Focal segmental glomerulosclerosis (FSGS) is a pathologic entity that is a common cause of nephrotic syndrome with severe proteinuria in both adults and children. Several causative genes have been identified in the pathogenesis of FSGS. Mutations of the transient receptor potential canonical-6 (TRPC6), a non-selective cation channel that is directly activated by diacylglycerol (DAG), cause a particularly aggressive form of FSGS. Angiotensin II, acting through its AT1 receptor, plays a critical role in generation of proteinuria and progression of kidney injury in a number of kidney diseases, including FSGS. Mounting evidence suggest the central role of TRPC6 and perhaps other TRPC channels in the pathogenesis of FSGS as well as of acquired forms of proteinuria such as diabetic nephropathy or hypertension. Identification of signaling pathways downstream of TRPC6 may provide novel targets for the treatment of proteinuria and prevent progression of podocyte injury.

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Mutation Analysis of <b><i>NPHS1 </i></b>in a Worldwide Cohort of Congenital Nephrotic Syndrome Patients

Cited by 33 publications

References 86 publications

Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort

Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort

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

Regulation of TRPC6 ion channels in podocytes — Implications for focal segmental glomerulosclerosis and acquired forms of proteinuric diseases

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