Clinical Information

Nephrotic syndrome (NS) is a kidney disorder characterized by proteinuria, hypoalbuminemia, and edema. Many conditions can cause NS, including diseases that only affect the kidney and other more systemic disorders such as diabetes or lupus. Focal segmental glomerulosclerosis (FSGS), a histologic finding characterized by sclerosis involving part of the kidney glomeruli, is commonly found in patients with NS.(1)

Approximately 85% of nephrotic syndrome is steroid sensitive, while the remaining 15% is steroid resistant (SRNS). SRNS may be genetic or nongenetic. Nongenetic causes of NS/FSGS may be due to a circulating factor causing generalized injury to podocytes, structural renal abnormalities, viral or drug-induced causes, or other stress on the kidney such as obesity, congenital heart disease, malignancy, or hypertension.(2)

Genetic SRNS may result from disease-causing variants in genes encoding renal-specific proteins (renal-limited) or syndromic conditions with extrarenal features.(2) Autosomal recessive forms of nonsyndromic SRNS typically present in childhood and are caused by disease-causing variants in nephrin (NPHS1), podocin (NPHS2), CD2AP, PLCE1, MYO1E, and multiple other genes. Autosomal dominant SRNS is typically adult onset and may be caused by disease-causing variants in TRPC6, ACTN4, INF2, and other genes. Variants in type IV collagen genes, known to cause Alport syndrome, may also be identified in patients with familial or sporadic SNRS and present later in adolescence or adulthood.

In syndromic forms of SRNS, extrarenal manifestations may be prominent and diagnostic, but in some cases, extrarenal features may be subtle or develop later in the disease course, such as in Denys-Drash syndrome (DDS) and Frasier syndrome caused by disease-causing variants in WT1.

Other genes included on this panel cover a broad spectrum of conditions that may display proteinuria, NS, or FSGS, either as an isolated feature or as part of a more systemic presentation, including genes associated with congenital disorders of glycosylation, Alport syndrome, coenzyme Q10 deficiency, and others.

This test also includes assessment of the G1 and G2 alleles of the APOL1 gene. The G1 and G2 alleles have been associated with increased risk for development or progression of nondiabetic chronic kidney diseases, including nonsyndromic SRNS.(3)

Despite some clinical and histologic overlap among the various categories of NS, management and prognosis may differ based on the underlying etiology. In particular, steroid sensitive NS may respond to treatment with corticosteroids, while SRNS, including those due to genetic causes, typically does not.(2) Therefore, identification of a genetic form of SRNS may impact evaluation for extra-renal manifestations, treatment decisions including transplantation, and genetic counselling.(4)