Genetic risk variants for childhood nephrotic syndrome and corticosteroid response.

Introduction: The etiology of most cases of nephrotic syndrome (NS) remains unknown, therefore patients are phenotypically categorized based on response to corticosteroid therapy as steroid sensitive NS (SSNS), or steroid resistant NS (SRNS). Genetic risk factors have been identified for SSNS from unbiased genome-wide association studies (GWAS), however it is unclear if these loci are disease risk loci in other forms of NS such as SRNS. Additionally, it remains unknown if these risk loci are associated with response to therapy.

Collapsing Focal Segmental Glomerulosclerosis in Siblings With Compound Heterozygous Variants in Expand the Spectrum of Kidney Phenotypes Associated With Nucleoporin Gene Mutations.

Background: Focal segmental glomerulosclerosis (FSGS) is a major cause of end stage kidney disease, with the collapsing form having the worst prognosis. Study of families with hereditary FSGS has provided insight into disease mechanisms.

Methods: In this report, we describe a sibling pair with mutations and collapsing FSGS (cFSGS).

Case Report: Unusual Aggregation of Different Glomerulopathies in a Family Resolved by Genetic Testing and Reverse Phenotyping.

Glomerular diseases (GDs) are a major cause of chronic kidney disease in children. The conventional approach to diagnosis of GDs includes clinical evaluation and, in most cases, kidney biopsy to make a definitive diagnosis. However, in many cases, clinical presentations of different GDs can overlap, leading to uncertainty in diagnosis and management even after renal biopsy.

A Rare Autosomal Dominant Variant in Regulator of Calcineurin Type 1 () Gene Confers Enhanced Calcineurin Activity and May Cause FSGS.

Background: Podocyte dysfunction is the main pathologic mechanism driving the development of FSGS and other morphologic types of steroid-resistant nephrotic syndrome (SRNS). Despite significant progress, the genetic causes of most cases of SRNS have yet to be identified.

Methods: Whole-genome sequencing was performed on 320 individuals from 201 families with familial and sporadic NS/FSGS with no pathogenic mutations in any known NS/FSGS genes.

Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome.

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.

Genetic Testing for Steroid-Resistant-Nephrotic Syndrome in an Outbred Population.

Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children and young adults. Despite advances in genomic science that have led to the discovery of >50 monogenic causes of SRNS, there are no clear guidelines for genetic testing in clinical practice. Using high throughput sequencing, we evaluated 492 individuals from 181 families for mutations in 40 known SRNS genes.

The Human FSGS-Causing R431C Mutation Induces Dysregulated PI3K/AKT/mTOR/Rac1 Signaling in Podocytes.

Background: We previously reported that mutations in the anillin () gene cause familial forms of FSGS. ANLN is an F-actin binding protein that modulates podocyte cell motility and interacts with the phosphoinositide 3-kinase (PI3K) pathway through the slit diaphragm adaptor protein CD2-associated protein (CD2AP). However, it is unclear how the mutations cause the FSGS phenotype.