Spectrum of NPHS1 and NPHS2 variants in egyptian children with focal segmental glomerular sclerosis: identification of six novel variants and founder effect.

The aim of this study is to screen for variants in NPHS1 and NPHS2, in a cohort of Egyptian children with steroid-resistant nephrotic syndrome (SRNS)/focal segmental glomerulosclerosis (FSGS) and compare the prevalence of such variants among other ethnic groups. The study included 25 patients: 21 children diagnosed clinically as steroid-resistant nephrotic syndrome and confirmed as FSGS by renal biopsy and four patients diagnosed as congenital nephrotic syndrome with FSGS. Mutational analysis revealed nine NPHS2 and NPHS1 variants in 13/25 patients with a pathogenic variant detection rate of 52%. NPHS2 variants were found in 8 patients (32%) while five patients from four unrelated families (20%) harbored variants in NPHS1 gene. Six variants were not described before including a likely founder NPHS2 variant in our population, c.596dupA (p.Asn199LysfsTer14). In conclusion, we reported the largest series of patients with SRNS/FSGS from Egypt and identified many novel NPHS1 and NPHS2 variants expanding their mutational spectrum. Further studies on a larger number of patients could provide new insights into the pathogenic mechanisms of SRNS/FSGS which might help in patient's management and prognosis.

An updated view of the pathogenesis of steroid-sensitive nephrotic syndrome.

Idiopathic nephrotic syndrome is the most common childhood glomerular disease. Most forms of this syndrome respond to corticosteroids at standard doses and are, therefore, defined as steroid-sensitive nephrotic syndrome (SSNS). Immunological mechanisms and subsequent podocyte disorders play a pivotal role in SSNS and have been studied for years; however, the precise pathogenesis remains unclear. With recent advances in genetic techniques, an exhaustive hypothesis-free approach called a genome-wide association study (GWAS) has been conducted in various populations. GWASs in pediatric SSNS peaked in the human leukocyte antigen class II region in various populations. Additionally, an association of immune-related CALHM6/FAM26F, PARM1, BTNL2, and TNFSF15 genes, as well as NPHS1, which encodes nephrin expressed in podocytes, has been identified as a locus that achieves genome-wide significance in pediatric SSNS. However, the specific mechanism of SSNS development requires elucidation. This review describes an updated view of SSNS pathogenesis from immunological and genetic aspects, including interactions with infections or allergies, production of circulating factors, and an autoantibody hypothesis.

Unilateral nephrectomy for young infants with congenital nephrotic syndrome of the Finnish type.

BACKGROUND: The management of congenital nephrotic syndrome of the Finnish type (CNF) is challenging. It is difficult to withdraw intravenous albumin infusions, resulting in long-term hospitalization. In addition, fatal hypotension after bilateral nephrectomy has been reported. In our center, we have performed unilateral nephrectomy during early infancy. METHODS: Infants diagnosed with CNF between 2011 and 2020 in our institution were enrolled. We examined the clinical course before and after unilateral nephrectomy and evaluated the effectiveness of this strategy. RESULTS: Seven patients (all showing NPHS1 mutations) were enrolled. All required daily intravenous albumin infusion via central venous catheter (CVC). Unilateral nephrectomy was performed at a median of 76 days of age (59-208 days). Surgical complications did not occur in any of patients. The mean albumin dose was decreased after unilateral nephrectomy (2.0 vs 0.4 g/kg/day; p = 0.02). Intravenous albumin infusion could be withdrawn at a median of 17 days, the CVC removed at a median of 21 days, and they discharged at a median of 82 days after unilateral nephrectomy. Although bacterial infections were noted seven times before unilateral nephrectomy, only one episode occurred after surgery. Four patients initiated peritoneal dialysis at two to three years of age and all of them underwent kidney transplantation thereafter. CONCLUSIONS: Unilateral nephrectomy during early infancy may be an effective treatment allowing for withdrawal from albumin infusion, prevention of complications, withdrawal from CVCs and shortening hospital stay for patients with CNF.

Congenital nephrotic syndrome: is early aggressive treatment needed? Yes.

Congenital nephrotic syndrome (CNS) was primarily considered one disease entity. Hence, one treatment protocol was proposed in the beginning to all CNS patients. Today, with the help of gene diagnostics, we know that CNS is a heterogeneous group of disorders and therefore, different treatment protocols are needed. The most important gene defects causing CNS are NPHS1, NPHS2, WT1, LAMB2, and PLCE1. Before active treatment, all infants with CNS died. It was stated already in the mid-1980s that intensive medical therapy followed by kidney transplantation (KTx) should be the choice of treatment for infants with severe CNS. In Finland, early aggressive treatment protocol was adopted from the USA and further developed for treatment of children with the Finnish type of CNS. The aim of this review is to state reasons for "early aggressive treatment" including daily albumin infusions, intensified nutrition, and timely bilateral nephrectomy followed by KTx at the age of 1-2 years.

[A case of severe congenital nephrotic syndrome secondary to NPHS1 mutation]. / Syndrome néphrotique congénital sévère avec mutation NPH S1.

The congenital nephrotic syndrome is a rare and severe pathology, and its management represents a real challenge for pediatric nephrologists. We report the case of a congenital nephrotic syndrome secondary to a homozygous mutation of the NPHS1. The young patient has a severe clinical course, and benefits of a management by anti-proteinuric treatment and a unilateral nephrectomy. This clinical case illustrates the difficulties of the management of a severe congenital nephrotic syndrome. To date, it is difficult to identify these patients beforehand because there is a poor correlation between the genotype and the phenotype of the NPHS1 mutation. There are two managements described in the literature: an early bilateral nephrectomy at 7 kg of weight with a renal transplant around 10 kg, versus a conservative management via an anti-proteinuric treatment and/or an unilateral nephrectomy. Current evidence is based on retrospective studies and the choice of a conservative approach versus early bilateral nephrectomy should take into account the severity of protein loss and its complications.

Le syndrome néphrotique congénital est une pathologie rare et sévère, dont la prise en charge représente un défi pour les néphrologues pédiatriques. Nous rapportons le cas d'un jeune patient présentant cette pathologie secondaire à une mutation homozygote du gène NPHS1. Il présente un tableau clinique sévère et bénéficie d'un traitement anti-protéinurique et d'une néphrectomie unilatérale. Ce cas clinique illustre les difficultés de la prise en charge des cas sévères, dont l'identification préalable est difficile à ce jour car la corrélation entre le génotype et le phénotype de la mutation NPHS1 est pauvre. Il existe deux prises en charges décrites dans la littérature : une néphrectomie bilatérale précoce vers 7 kg de poids et une greffe rénale vers 10 kg, ou bien une prise en charge conservative via un traitement anti-protéinurique et/ou une néphrectomie unilatérale permettant de postposer la greffe. Les données actuelles n'étant basées que sur des études rétrospectives, le choix entre une approche conservative et une néphrectomie bilatérale précoce doit prendre en compte la sévérité de la déperdition protéique et ses complications.

A comprehensive analysis of NPHS1 gene mutations in patients with sporadic focal segmental glomerulosclerosis.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is still one of the common causes of refractory nephrotic syndrome. Nephrin, encoded by podocyte-specific NPHS1 gene, participated in the pathogenesis of FSGS. The sites of NPHS1 mutations in FSGS is not clarified very well. In this study, we investigated the specific mutations of NPHS1 gene in Chinese patients with sporadic FSGS. METHODS: A total of 309 patients with sporadic FSGS were collected and screened for NPHS1 mutations by second-generation sequencing. The variants were compared with those extracted from 2504 healthy controls in the 1000 Genomes Project. The possible pathogenic roles of missense variants were predicted by three different software. We also compared these candidate causal mutations with those summarized from the previous studies. RESULTS: Thirty-two genetic mutations of NPHS1 gene were identified in FSGS patients, including 12 synonymous mutations, 17 missense mutations, 1 splicing mutation, and 2 intron mutations, of which c.G3315A (p.S1105S) was the most common variant (261/309). A novel missense mutation c.G2638 T (p.V880F) and a novel splicing mutation 35830957 C > T were identified in FSGS patients. The frequencies of the four synonymous mutations (c.C294T [p.I98I], c.C2223T [p.T741 T], c.C2289T [p.V763 V], c.G3315A [p.S1105S]) were much higher in FSGS patients than in controls. The frequencies of the four missense mutations (c.G349A [p.E117K], c.G1339A [p.E447K], c.G1802C [p.G601A], c.C2398T [p.R800C]) were much higher and one (c.A3230G [p.N1077S]) was lower in FSGS patients than in controls. Five missense mutations, c.C616A (p.P206T), c.G1802C (p.G601A), c.C2309T (p.P770L), c.G2869C (p.V957 L), and c.C3274T (p.R1092C), were predicted to be pathogenic mutations by software analysis. CONCLUSIONS: NPHS1 gene mutations were quite common in sporadic FSGS patients. We strongly recommend mutation analysis of the NPHS1 gene in the clinical management of FSGS patients.

Genetics and ESKD Disparities in African Americans.

African Americans have a 2- to 4-fold greater incidence of end-stage kidney disease (ESKD) than whites, which has long raised the possibility of a genetic cause for this disparity. Recent advances in genetic studies have shown a causal association of polymorphisms at the apolipoprotein L1 gene (APOL1) with the markedly increased risk for the nondiabetic component of the overall disparity in ESKD in African Americans. Although APOL1-associated kidney disease is thought to account for a substantial proportion of ESKD in African Americans, not all the increased risk for ESKD is accounted for, and a complete cataloging of disparities in genetic causes of ESKD eludes our current understanding of genetic-associated kidney disease. Genetic testing aids the screening, diagnosis, prognosis, and treatment of diseases with a genetic basis. Widespread use of genetic testing in clinical practice is limited by the small number of actionable genetic variants, limited health literacy of providers and patients, and underlying complex ethical, legal, and social issues. This perspective reviews racial and ethnic differences associated with genetic diseases and the development of ESKD in African Americans and discusses potential uncertainties associated with our current understanding of penetrance of genetically linked kidney disease and population-attributable risk percent.

Management of children with congenital nephrotic syndrome: challenging treatment paradigms.

BACKGROUND: Management of children with congenital nephrotic syndrome (CNS) is challenging. Bilateral nephrectomies followed by dialysis and transplantation are practiced in most centres, but conservative treatment may also be effective. METHODS: We conducted a 6-year review across members of the European Society for Paediatric Nephrology Dialysis Working Group to compare management strategies and their outcomes in children with CNS. RESULTS: Eighty children (50% male) across 17 tertiary nephrology units in Europe were included (mutations in NPHS1, n = 55; NPHS2, n = 1; WT1, n = 9; others, n = 15). Excluding patients with mutations in WT1, antiproteinuric treatment was given in 42 (59%) with an increase in S-albumin in 70% by median 6 (interquartile range: 3-8) g/L (P < 0.001). Following unilateral nephrectomy, S-albumin increased by 4 (1-8) g/L (P = 0.03) with a reduction in albumin infusion dose by 5 (2-9) g/kg/week (P = 0.02). Median age at bilateral nephrectomies (n = 29) was 9 (7-16) months. Outcomes were compared between two groups of NPHS1 patients: those who underwent bilateral nephrectomies (n = 25) versus those on conservative management (n = 17). The number of septic or thrombotic episodes and growth were comparable between the groups. The response to antiproteinuric treatment, as well as renal and patient survival, was independent of NPHS1 mutation type. At final follow-up (median age 34 months) 20 (80%) children in the nephrectomy group were transplanted and 1 died. In the conservative group, 9 (53%) remained without dialysis, 4 (24%; P < 0.001) were transplanted and 2 died. CONCLUSION: An individualized, stepwise approach with prolonged conservative management may be a reasonable alternative to early bilateral nephrectomies and dialysis in children with CNS and NPHS1 mutations. Further prospective studies are needed to define indications for unilateral nephrectomy.

Detailed clinical manifestations at onset and prognosis of neonatal-onset Denys-Drash syndrome and congenital nephrotic syndrome of the Finnish type.

BACKGROUND: Neonatal-onset Denys-Drash syndrome (NODDS) is a distinctive clinical entity and has a poor renal and life outcome. Early diagnosis of NODDS is important for managing disorders of sexual development and determining assigned gender. Although patients with NODDS and congenital nephrotic syndrome of the Finnish type (CNF) present with nephrotic syndrome in neonatal life or infancy, the clinical course of NODDS and factors distinguishing these diseases at onset is unknown. METHODS: We performed a retrospective cohort study of patients with NODDS and CNF between 1997 and 2017. Patients with nephrotic syndrome and WT1 or NPHS1 mutations with neonatal onset (within 30 days) were eligible. RESULTS: We studied eight patients with NODDS and 15 with CNF. The median serum creatinine level at onset in the NODDS group was significantly higher (1.85 mg/dL) than that in the CNF group (0.15 mg/dL; P = 0.002). The median placental/fetal weight ratio in the NODDS and CNF group was 41.8% and 21.0%, respectively (P = 0.001). Kaplan-Meier analysis showed that the median number of days for progression to ESRD from onset in the NODDS and CNF groups was 6 and 910 days, respectively (P < 0.001). All patients in the NODDS group were alive at follow-up. Only one patient in the CNF group died of cardiac complications during follow-up. CONCLUSION: CNS, renal dysfunction at onset, and a relatively large placenta are prominent signs of NODDS. Prognosis for patients with NODDS is satisfactory if appropriate and active management is performed.

The Role of p.Ser1105Ser (in NPHS1 Gene) and p.Arg548Leu (in PLCE1 Gene) with Disease Status of Vietnamese Patients with Congenital Nephrotic Syndrome: Benign or Pathogenic?

Background and Objectives: Congenital nephrotic syndrome (CNS), a genetic disease caused by mutations in genes on autosomes, usually occurs in the first three months after birth. A number of genetic mutations in genes, which encode for the components of the glomerular filtration barrier have been identified. We investigated mutations in NPHS1, NPHS2, PLCE1 (NPHS3), and WT1 genes that relate to the disease in Vietnamese patients. Materials and Methods: We performed genetic analysis of two unrelated patients, who were diagnosed with CNS in the Vietnam National Children's Hospital with different disease status. The entire coding region and adjacent splice sites of these genes were amplified and sequenced using the Sanger method. The sequencing data were analyzed and compared with the NPHS1, NPHS2, PLCE1, and WT1 gene sequences published in Ensembl (ENSG00000161270, ENSG00000116218, ENSG00000138193, and ENSG00000184937, respectively) using BioEdit software to detect mutations. Results: We detected a new variant p.Ser607Arg and two other (p.Glu117Lys and p.Ser1105Ser) in the NPHS1 gene, as well as two variants (p.Arg548Leu, p.Pro1575Arg) in the PLCE1 gene. No mutations were detected in the NPHS2 and WT1 genes. Patient 1, who presented a heterozygous genotype of p.Ser1105Ser and p.Arg548Leu had a mild disease status but patient 2, who presented a homozygous genotype of these alleles, had a severe phenotype. Conclusions: These results suggest that variants p.Ser1105Ser (in NPHS1 gene) and p.Arg548Leu (in PLCE1 gene) in the homozygous form might play a role in the development of the disease in patients.

Novel variations in NPHS1 gene in children of South Indian population and its association with primary nephrotic syndrome.

Mutations in NPHS1 can lead to disruption of the filtration barrier and cause proteinuria in nephrotic syndrome (NS). The aim of the study was to evaluate NPHS1 mutations, its susceptibility to the disease, and their association in children with steroid-resistant NS; mutation frequency of 9% was observed in patients with steroid-resistant NS, of which, six mutations and two single-nucleotide polymorphisms observed in the study population were found to be novel.

Cyclosporine A responsive congenital nephrotic syndrome with single heterozygous variants in NPHS1, NPHS2, and PLCE1.

BACKGROUND: Congenital nephrotic syndrome (CNS) is primarily a monogenetic disease, with the majority of cases due to changes in five different genes: the nephrin (NPHS1), podocin (NPHS2), Wilms tumor 1 (WT1), laminin ß2 (LAMB2), and phospholipase C epsilon 1 (PLCE1, NPHS3) gene. Usually CNS is not responsive to immunosuppressive therapy, but treatment with ACE inhibitors, AT1 receptor blockade and/or indomethacin can reduce proteinuria. If the disease progresses to end-stage renal disease, kidney transplantation is the therapy of choice. CASE-DIAGNOSIS: Here, we present the case of a 4-month-old girl with congenital nephrotic syndrome. Upon admission, the patient presented with life-threatening anasarca, hypoalbuminemia, proteinuria, and impaired growth. There was no evidence of an infectious or immunological etiology. The genetic evaluation revealed a heterozygous variant in NPHS1 (p.Arg207Trp), in NPHS2 (p.Ser95Phe) as well as in PLCE1 (p.Ala1045Ser) and did not explain CNS. In addition to daily parenteral albumin infusions plus furosemide, a pharmacological antiproteinuric therapy was started to reduce protein excretion. Based on the genetic results, immunosuppressive therapy with prednisolone was initiated, but without response. However, following cyclosporine A treatment, the patient achieved complete remission and now has good renal function, growth, and development. CONCLUSIONS: A profound search for the cause of CNS is necessary but has its limitations. The therapeutic strategy should be adapted when the etiology remains unclear.

Gene mutation analysis in 12 Chinese children with congenital nephrotic syndrome.

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.

Whole exome sequencing identifies multiple diagnoses in congenital glaucoma with systemic anomalies.

The genetic basis of congenital glaucoma with systemic anomalies is largely unknown. Whole exome sequencing (WES) in 10 probands with congenital glaucoma and variable systemic anomalies identified pathogenic or likely pathogenic variants in three probands; in two of these, a combination of two Mendelian disorders was found to completely explain the patients' features whereas in the third case only the ocular findings could be explained by the genetic diagnosis. The molecular diagnosis for glaucoma included two cases with compound heterozygous or homozygous pathogenic alleles in CYP1B1 and one family with a dominant pathogenic variant in FOXC1; the second genetic diagnosis for the additional systemic features included compound heterozygous mutations in NPHS1 in one family and a heterozygous 18q23 deletion in another pedigree. These findings show the power of WES in the analysis of complex conditions and emphasize the importance of CYP1B1 screening in patients with congenital glaucoma regardless of the presence/absence of other systemic anomalies.

Timing of renal replacement therapy does not influence survival and growth in children with congenital nephrotic syndrome caused by mutations in NPHS1: data from the ESPN/ERA-EDTA Registry.

BACKGROUND: Congenital nephrotic syndrome (CNS) of the Finnish type, NPHS1, is the most severe form of CNS. Outcomes of renal replacement therapy (RRT) in NPHS1 patients in Europe were analysed using data from the ESPN/ERA-EDTA Registry. As NPHS1 is most prevalent in Finland and the therapeutic approach differs from that in many other countries, we compared outcomes in Finnish and other European patients. METHODS: NPHS1 mutations were confirmed in 170 children with CNS who initiated RRT (dialysis or renal transplantation) between 1991 and 2012. Finnish (n = 66) and non-Finnish NPHS1 patients (n = 104) were compared with respect to treatment policy, age at first RRT and renal transplantation (RTX), patient and graft survival, estimated glomerular filtration rate (eGFR) and growth. Age-matched patients with congenital anomalies of the kidney and urinary tract (CAKUT) served as controls. RESULTS: Finnish NPHS1 patients were significantly younger than non-Finnish patients, both at the start of RRT and at the time of RTX. We found similar overall 5-year patient survival on RRT (91 %) and graft survival (89 %) in both NPHS1 groups and CAKUT controls. At the start of RRT, height standard deviation score (SDS) was higher in Finnish patients than in non-Finnish patients (mean [95 % CI]: -1.31 [-2.13 to -0.49] and -3.0 [-4.22 to -1.91], p < 0.01 respectively), but not at 5 years of age. At 5 years of age height and body mass index (BMI) SDS were similar to those of CAKUT controls. CONCLUSIONS: Overall, 5-year patient and graft survival of both Finnish and non-Finnish NPHS1 patients on RRT were excellent and comparable with CAKUT patients with equally early RRT onset and was independent of the timing of RRT initiation and RTX.

NPHS1 gene mutations confirm congenital nephrotic syndrome in four Brazilian cases: A novel mutation is described.

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.

Congenital nephrotic syndrome with a novel NPHS1 mutation.

Congenital nephrotic syndrome of the Finnish type (CNF) is a rare autosomal recessive disorder. The incidence of CNF is relatively high in Finland but considerably lower in other countries. We encountered a male newborn with CNF, associated with compound heterozygous mutations in nephrosis 1, congenital, Finnish type (NPHS1). The patient was admitted to hospital as a preterm infant. Physical and laboratory findings fulfilled the diagnostic criteria of nephrotic syndrome, and were compatible with a diagnosis of CNF, but there was no family history of the disease. On genetic analysis of NPHS1 a paternally derived heterozygous frame-shift mutation caused by an 8 bp deletion, resulting in a stop codon in exon 16 (c.2156-2163 delTGCACTGC causing p.L719DfsX4), and a novel, maternally derived nonsense mutation in exon 15 (c.1978G>T causing p.E660X) were identified. Early genetic diagnosis of CNF is important for proper clinical management and appropriate genetic counseling.

Congenital Nephrotic Syndrome - Finish Type.

INTRODUCTION: Identification of the NPHS1 gene, which encodes nephrin, was followed by many studies demonstrating its mutation as a frequent cause of congenital nephrotic syndrome (CNS). While this gene is found in 98% of Finnish children with this syndrome, non-Finnish cases have lower level of incidence ranging from 39 to 80%. CASE REPORT: This report describes the clinical presentation of a two-week-old neonate who presented with periorbital and lower extremities edema, abdominal distention, heavy proteinuria, serum hypoproteinemia and failure to thrive. Genetic analysis revealed NHPS1 gene mutation leading to CNS-Finnish type diagnosis. CONCLUSION: Through this case we want to create awareness about diagnosis and treatment challenges in developing countries for rare congenital diseases.

Congenital nephrotic syndrome of NPHS1 associated with cardiac malformation.

Congenital nephrotic syndrome (CNS) is a rare disease inherited as an autosomally recessive trait and defined as proteinuria manifesting at birth or in the first 3 months of life. The classical form is the Finnish type of CNS (CNF), which is caused by mutations in the nephrin gene (NPHS1). The classical findings include prematurity, large placenta and massive proteinuria. Minor cardiac findings have been reported as a minor functional disorder but CNS with major cardiac malformation is rare. Here we report the case of a Turkish child with CNS with small indel mutation (c.614_621delCACCCCGGinsTT) in exon 6 of NPHS1 and also major cardiac malformation who did not develop end-stage renal disease until the age of 5 years.