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Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide. In addition to hematuria, proteinuria is observed in a considerable proportion of patients with IgAN and has proven to be a strong risk factor for disease progression. Although the exact pathogenesis of IgAN is still unclear, genetic factors are widely considered to play a role in its occurrence and development. Here, we investigated a large IgAN-associated pedigree of 47 members belonging to six generations. Two members of the family who presented with proteinuria and hematuria were diagnosed with IgAN through renal biopsy. Four other members also exhibited proteinuria or hematuria but without renal biopsy. Using whole-exome sequencing, we identified a likely pathogenic variant in WT1 (c.1397C>T; p.Ser466Phe) that cosegregated with proteinuria in the affected family members. In addition, another pathogenic variant in NPHS1 (c.3478C>T; p.Arg1160Ter) was identified; however, it did not cosegregate with abnormal proteinuria. Compared to individuals in the pedigree with only one heterozygous WT1 variant (c.1397C>T; p.Ser466Phe), the proband and her younger brother carried an additional WT1 variant (c.1433-10G>A) and presented with a more severe phenotype and rapid progression to end-stage kidney disease. Our findings suggest the WT1 missense variant (c.1397C>T; p.Ser466Phe)-induced primary podocyte injury might contribute to the proteinuria phenotype and IgAN progression in this pedigree.

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Objective@#To explore the genetic basis for a fetus suspected for congenital nephrotic syndrome of Finland (CNF).@*Methods@#Genomic DNA was extracted from peripheral and umbilical cord blood samples derived from both parents and the fetus. Potential variants were detected by using next-generation sequencing. Suspected variants were confirmed by Sanger sequencing.@*Results@#The fetus was found to carry compound heterozygous variants c. 1440+ 1G>A and c. 925G>T of the NPHS1 gene, which were respectively inherited from its mother and father.@*Conclusion@#Identification of the compound heterozygous NPHS1 variants has enabled diagnosis of CNF in the fetus and genetic counseling for the affected family.

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BACKGROUND: Congenital nephrotic syndrome (CNS) is characterised by increased proteinuria, hypoproteinemia, and edema beginning in the first 3 months of life. Recently, molecular genetic studies have identified several genes involved in the pathogenesis of CNS. A systematic investigation of the genes for CNS in China has never been performed; therefore, we conducted a mutational analysis in 12 children with CNS,with the children coming from 10 provinces and autonomous regions in China. METHODS: Twelve children with CNS were enrolled from 2009 to 2016. A mutational analysis was performed in six children by Sanger sequencing in eight genes (NPHS1, NPHS2, PLCE1, WT1, LAMB2, LMXIB, COQ6 and COQ2) before 2014, and whole-exome sequencing was used from 2014 to 2016 in another six children. Significant variants that were detected by next generation sequencing were confirmed by conventional Sanger sequencing in the patients' families. RESULTS: Of the 12 children, eight patients had a compound heterozygous NPHS1 mutation, one patient had a de novo mutation in the WT1 gene, and another patient with extrarenal symptoms had a homozygous mutation in the COQ6 gene. No mutations were detected in genes NPHS2, PLCE1, LAMB2, LMXIB, and COQ2 in the 12 patients. CONCLUSIONS: This study demonstrates that the majority of CNS cases (67%, 8/12 patients) are caused by genetic defects, and the NPHS1 mutation is the most common cause of CNS in Chinese patients. A mutational analysis of NPHS1 should be recommended in Chinese patients with CNS in all exons of NPHS1 and in the intron-exon boundaries.

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This descriptive and comparative review examines the changing epidemiology, treatment, renal and patient outcome of childhood nephrotic syndrome (NS) in tropical Africa (TpAfr). In the 1960s to 1980s, corticosteroid-resistant non-minimal change disease (nMCD) including quartan malaria nephropathy (QMN) was the dominant renal histopathology type. The overall incidence of NS was 0.35-1.34% of hospital admissions. Median age at onset of NS ranged between 4.0 and 12.0 years while the mean (SD) age range was 5.8 (3.8) to 10.3 (4.8) years across studies. The male: female ratio was 1.6:1.0. The overall mean (SD) incidence of idiopathic minimal change disease (MCD) [21.6 (18.6%)] compared with idiopathic nMCD [59.1 (25.7%)] demonstrates significant dominance of the latter (p = 0.0001). Post-1989, the following mean (SD) incidences of histopathological types were: MCD 20.4 (17.7%), focal segmental glomerulosclerosis 39.0 (26.3%), membranoproliferative glomerulonephritis 25.4 (16.8%), proliferative glomerulonephritis 16.7 (27.0%) and membranous nephropathy 7.4 (4.5%). While the mean (SD) proportion of steroid resistance (SR) [73.5 (19.2%)] was significantly greater than the mean complete remission (CR) [26.5 (19.2%)] during 1960-1989 (p=0.005), mean (SD) SR [27.4 (25.3%)] was significantly lower than mean (SD) CR [66.1 (28.0%)] post-1989 (p < 0.001). Unlike QMN, hepatitis B virus, HIV infection, sickle cell disease and systemic lupus erythematosus are now increasingly being associated with NS in TpAfr. Mean (SD) renal survival post-1989 was 58.3 (37.0%) while all-cause mortality was 9.8%. Children with NS now survive better than before, reflecting improved access to healthcare and transition to a clinical pattern favouring idiopathic NS and increased sensitivity to corticosteroids.

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AIM: Autosomal recessive mutations in NPHS1 gene are a common cause of congenital nephrotic syndrome (CNS). The disorder is characterized by massive proteinuria that manifests in utero or in the neonatal period during the first 3 months of life. NPHS1 encodes nephrin, a member of the immunoglobulin family of cell adhesion molecules and the main protein expressed at the renal slit diaphragm. Currently, there are approximately 250 mutations described in the NPHS1 gene distributed among all nephrin domains. The main objective of this study was to perform the analysis of the NPHS1 gene in patients with congenital nephrotic syndrome in order to determine the molecular cause of the disease. METHODS: Direct sequencing of NPHS1 gene in four children was performed. RESULTS: Each patient was heterozygous for two pathogenic mutations disclosing the molecular cause of the disease in 100% of the cases. We identified six different mutations, consisting of one in-frame deletion, one frameshift, and four missense substitutions. The p.Val736Met mutation that is described here for the first time was considered pathogenic by different mutation predictive algorithms. Regardless of the type of mutation, three patients had a bad outcome and died CONCLUSIONS: Despite the small size of the cohort, this study contributed to the increasing number of deleterious mutations in the NPHS1 gene by describing a new mutation. Also, since we identified NPHS1 pathogenic mutations as the cause of the disease in all cases analyzed, it might be a frequent cause of CNS in the South Eastern region of Brazil, although the analysis of a larger sample is required to obtain more indicative epidemiological data.

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Objective To elucidate the mutations of NPHS1 gene in children with sporadic steroid-resistant nephrotic syndrome (SRNS) in Southern Chinese Han ethnic group.Methods Peripheral blood samples were collected for genetic analysis from 40 patients with sporadic SRNS and 50 healthy volunteers as control.Genomic DNA was isolated from peripheral blood leucocytes.Twenty-nine exons and exon-intron boundaries of the NPHS1 gene were amplified by polymerase chain reaction.Mutational analysis was performed by DNA sequencing directly.Results Seven variants,928G＞A(D310N),2677A＞G (T893A),2869G＞C (V957L),IVS8+30C＞T,IVS21+14G＞A,IVS25-23C＞T and *142T＞C,of NPHS1 gene were found in 6 of 40 children with sporadic SRNS,whereas they were not found in 50 healthy controls.2677A ＞G,IVS8 +30C ＞T,IVS21 +14G＞A,IVS25-23C ＞T and *142T＞C were novel.Moreover,thirteen already reported NPHS1 polymorphisms,294C＞T,349G＞A,IVS3+15C＞T,IVS3+61A＞G,803G＞A,IVS8+68A＞G,1339G ＞A,1802G ＞C,2223C ＞T,2289C ＞T,IVS24 +36C ＞T,3315G＞A and IVS27 +45C ＞T,were detected in some patients and controls. Conclusions NPHS1 mutations in 6 of 40 children with sporadic SRNS in Southern Chinese Han ethnic group (15％) are detected.NPHS1 mutations are existed in Southern Chinese children,so it is necessary to perform the mutation analysis of NPHS1 gene in those children patients.

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Congenital nephrotic syndrome is defined as nephrotic syndrome which manifests in utero or during the first 3 months of life. The prototype of congenital nephrotic syndrome is congenital nephrotic syndrome of Finnish type (CNF, OMIM #602716), which is caused by loss-of-function mutations of the nephrin gene (NPHS1). There have been few clinical case reports of CNF in Korea, but none of which was confirmed by genetic study. Here, we report two children with congenital nephrotic syndrome. Genetic analysis of the NPHS1 gene revealed compound heterozygous frame-shifting mutations (c.2156_2163 delTGCACTGC causing p.L719DfsX4 and c.3250_3251insG causing p.V1084GfsX12) in one patient and a missense mutation (c.1381G>A causing p.R460Q) and a nonsense mutation (c.2442C>G causing p.Y814X) in the other patient. The nonsense mutation was novel. The clinical courses of the patients were typical of CNF. This is the first report of genetically confirmed CNF in Korea to date. The early genetic diagnosis of CNF is important for proper clinical management of the patients and precise genetic counseling of the families.

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Congenital nephrotic syndrome is defined as nephrotic syndrome which manifests in utero or during the first 3 months of life. The prototype of congenital nephrotic syndrome is congenital nephrotic syndrome of Finnish type (CNF, OMIM #602716), which is caused by loss-of-function mutations of the nephrin gene (NPHS1). There have been few clinical case reports of CNF in Korea, but none of which was confirmed by genetic study. Here, we report two children with congenital nephrotic syndrome. Genetic analysis of the NPHS1 gene revealed compound heterozygous frame-shifting mutations (c.2156_2163 delTGCACTGC causing p.L719DfsX4 and c.3250_3251insG causing p.V1084GfsX12) in one patient and a missense mutation (c.1381G>A causing p.R460Q) and a nonsense mutation (c.2442C>G causing p.Y814X) in the other patient. The nonsense mutation was novel. The clinical courses of the patients were typical of CNF. This is the first report of genetically confirmed CNF in Korea to date. The early genetic diagnosis of CNF is important for proper clinical management of the patients and precise genetic counseling of the families.

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