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

Age of onset distribution (in years) for 1589 of 1783 examined SRNS families. The displayed 1589 families represent the number of families with available data for age of onset of proteinuria <18 years. (A) Red curve and histograms represent the number of families in each age of onset (years) of SRNS for 1093 families without molecular genetic diagnosis. Blue curve and histograms show number of 496 families with causative mutations identified for each age of onset. (B) Graph indicates percentage of solved families per year of age of onset (from A). Black dotted line represents a binomial fit of age-related percent of families with causative mutation. (Data are not displayed for 72 individuals who were older than 17 years at onset of SRNS and for 122 families with no available information for age of onset. In families with >1 affected family member, the mean age of onset from all affected individuals was used.)

Detection of the causative mutation in 502 families in an international cohort of 1617 families with SRNS in 21 SRNS-causing genes in relation to age of onset of proteinuria in clinically relevant age groups. The displayed 502 families represent the number of families with detected causative mutation and available data for age of onset of proteinuria <26 years. (A) Percentage of families with causative mutation detected per gene per age group. Histograms indicate fraction (in percentage) of families with causative gene detected in n families per families examined (on top of histograms) per age group. (B) Percentages shown in A are represented by separate bars to highlight distribution across age groups as further delineated in C. Note that mutations in NPHS1 or LAMB2 cause early-onset SRNS, whereas mutations in INF2 or TRPC6 cause late-onset SRNS. (C) Percentages of families with causative mutation detected (from B) are interconnected by lines between age groups and shown in different colors for each causative gene (lower panel for recessive genes, upper panel for dominant genes). NPHS1 mutations (red) have an early age of onset and are rarely found in patients older than 6 years. The dominant genes INF2 and TRPC6 manifest in early adulthood and WT1 (black) shows a biphasic distribution (upper panel). (For families with detected disease-causing mutation, data are not shown for 11 families where no age of onset was available, and for 10 families with an age of onset older than 25 years. For families with no detection of the disease-causing mutation, data are not displayed for 111 families for whom no data for age of onset were available and for 34 families with age of onset older than 25 years. In families with >1 affected family member the mean age of onset from all affected individuals was calculated.).