A 28-gene test for kidney disease

dialysis nephrotic syndrome
Understanding the genetic causes of nephrotic syndrome could lead to better drug treatments that reduce the need for dialysis or a kidney transplant. (Image: Wikimedia Commons)

Nephrotic syndrome is one of the worst diseases a child can have. It strikes the filtering units of the kidney, structures known as glomeruli. There’s no good treatment: Steroids are the main therapy used, but 20 percent of cases are steroid-resistant. In the syndrome’s most severe form, focal segmental glomerulosclerosis (FSGS), children are forced onto chronic dialysis and often require a kidney transplant—often only to have their disease recur in the new organ.

Until recently, no one knew what caused nephrotic syndrome; the first causative gene was identified just a dozen years ago. The lab of Friedhelm Hildebrandt, MD, PhD, at Boston Children’s Hospital is one of a handful that’s been chipping away at the others.

Hildebrandt receives, on average, one blood sample a day from patients all over the world. Now, with next-generation DNA-sequencing technology, his team’s discoveries are accelerating. One recently completed study, not yet published, tested more than 1,700 families for 26 genes known to be associated with steroid-resistant nephrotic syndrome.

“We can now test 1,000 individuals in three weeks for the 26 genes at a cost of $30 per person,” says Hildebrandt, whose research is supported by the NIH, the Howard Hughes Medical Institute and NephCure. “We were able to find a single-gene cause for nephrotic syndrome in 30 percent of our cases.”

nephrotic syndrome
Focal segmental glomerulosclerosis (FSGS) (Nephron/Wikimedia Commons)

In all, more than 30 genes have been discovered. This week, Claritas Genomics, a genetic diagnostics company spun off from Boston Children’s in early 2013, announced a clinical-grade, 28-gene test panel based on the Hildebrandt lab’s discoveries. (Update: As of March 2017, the panel now covers 42 genes.) The panel, licensed from Boston Children’s, joins Claritas’s menu of more than 100 genetic tests, including a next-generation assay analyzing 614 genes associated with neurologic disorders and a microarray test for patients with autism, developmental delay or intellectual disability.

In the meantime, Hildebrandt’s findings are helping to clarify the biology of nephrotic syndrome. “For the first time, things start to converge,” he says. “A whole avenue is opening where one could envision developing new treatments.”

Several of the genes, for example, cause a defect in synthesis of coenzyme Q10—a natural enzyme that’s also readily available as a food supplement. “Children with mutations in these genes can potentially have nephrotic syndrome reversed,” says Hildebrandt.

That advance came with the help of powerful allies: zebrafish. Mutations in the coenzyme Q10 pathway, as well another pathway involving RhoA signaling, cause the fish to develop swelling around their eyes much like that seen in children with nephrotic syndrome. Potential therapeutics can then be tested in large-scale zebrafish assays to see if that swelling—as well as abnormalities in the glomeruli—can be reversed.  Such testing indicates that mutations in the RhoA pathway may also be amenable to drug treatment.

Even with a clinical-grade test on the market, the gene hunt isn’t over. “There’s probably several dozen more genes out there, each of which is rare, but they add up,” Hildebrandt says.

  • tuhumom

    Very interesting discussion. As a former kidney
    disease sufferer, I know how frustrating it can be to find
    answers. Just wanted to share a link that helped me out a lot when I
    was struggling to get better:

    http://journalofnaturalhealth.com/kidney/kidneyhealth.html

    Best of luck to everyone!