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Resolving key details of polycystic kidney disease genetics

Researchers helped clarify what genetic variations can cause polycystic kidney disease (PKD) by examining specific gene sequences in more than 170,000 people in a regional healthcare system who agreed to participate. In PKD, numerous kidney cysts form that interfere with the organ’s function. As the disease progresses it often leads to kidney failure and complications such as high blood pressure, cysts in the liver, and problems with blood vessels in the brain and heart. The most common form of PKD—autosomal dominant PKD, or ADPKD—usually occurs when someone has a disease-causing variant in either the gene PKD1 or the gene PKD2. However, although some specific variations in these genes are known to cause disease, many other PKD1 and PKD2 variants are of uncertain significance. Importantly, a significant number of people with ADPKD have been found to have only normal versions of PKD1 and PKD2, and previous research has implicated rare variants in at least 10 other genes as potentially being able to cause the disease.

To shed more light on the genetic causes of ADPKD, scientists used a technique that allowed them to zero in on the key portions of each gene previously suggested to have a role in causing the disease. They examined the gene sequences in consenting participants—more than 170,000 people—among whom 235 had a diagnosis of ADPKD. This allowed them to identify genetic variants in PKD1 and PKD2 that truly are likely to cause ADPKD—including previously unknown variations—while ruling out some of the previous suspects. Variations in PKD1 turned out to be causing the disease in a bit more than half of those with ADPKD, while PKD2 variations accounted for 14 percent, and variations in other genes accounted for an additional 8 percent. Importantly, it was not possible to identify the genetic cause of ADPKD in almost a quarter of the participants with the disease, suggesting there is much more to discover about its causes. Because 93 percent of the study participants were of European ancestry, it will be important to extend this research in a study with a more diverse group of participants. These findings potentially improve on scientists’ ability to predict who will develop ADPKD, and who might benefit from treatments currently in development.

Chang AR, Moore BS, Luo JZ,….Mirshahi T. Exome sequencing of a clinical population for autosomal dominant polycystic kidney disease. JAMA 328: 2412–2421, 2022.

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