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

Abstract

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.

Focal Segmental Glomerulosclerosis

“…The answer to this question remains unclear. With regard to pediatric patients, Hildebrandt and coworkers (75) have suggested that every family with a child who has FSGS deserves to be offered an opportunity to have a genetic diagnosis (RE). Benefits of this approach may include a guide to appropriate therapy (e.g., avoidance of glucocorticoids except for in genetic forms that may be responsive and coenzyme Q10 therapy for particular mitochondrial mutations), prognosis (typical native kidney outcomes and likelihood of transplant recurrence), and family issues (identification of disease in other family members and prenatal testing).…”

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

“…PLCe1 was also shown to modulate adrenergic receptor-dependent cardiac contraction and to inhibit cardiac hypertrophy (22,23). Patients with focal segmental glomerulosclerosis have been found to have loss-of-function mutations in PLCe1, and PLCe1 itself interacts with transient receptor potential channel 6 (24)(25)(26)(27). Even more intriguing is the fact that a genome-wide association study identified the susceptibility loci for dengue shock syndrome at PLCe1 (28).…”

Need to Reclassify Etiologies of ESRD on the CMS 2728 Medical Evidence Report

“…Identification of the apolipoprotein L1 gene (APOL1)-associated spectrum of nondiabetic nephropathy in patients with recent African ancestry supports the need to remove "hypertension" as the cause of ESRD in those with mild to moderately elevated BPs. Detection of genes underlying steroid-resistant nephrotic syndrome and autosomal dominant tubulointerstitial forms of nephropathy further supports the need to update the nomenclature, particularly after genetic testing becomes widely available (8,9).…”