Only use in course of reposrting about this paper or the Genomics platform at Max Delbrück Center. Credit: David Ausserhofer, Max Delbrück Center
Key points:
- Researchers turned to long-read sequencing for answers when patients with a rare kidney disease presented with more severe symptoms than typical.
- While they did not find answers for the family, the team did discover new structural variants.
- The study results shed much needed light on the causes of the rare disease.
Bartter syndrome type 3 is a rare kidney disease characterized by hypokalemic metabolic alkalosis. But when a family entered University Hospital Cologne (Germany) with much more severe joint changes than typically seen, Dr. Bodo Beck knew there was more going on.
People with Bartter syndrome type 3 lack the CLCNKB gene, which is responsible for a specific chloride channel. The electrolyte balance becomes disrupted because the kidneys cannot reabsorb important nutrients and salts back into the bloodstream during filtration and urine production. In addition to the absence of the CLCNKB gene, Beck suspected there might be more extensive genome deletions that would explain the severe clinical picture.
Because of its ability to accurately read much longer stretches of DNA in a single run, researchers at the Max Delbrück Center for Molecular Medicine turned to long-read sequencing for answers.
Working with 32 patients from kidney centers in Cologne, Marburg, Münster and London, the team identified various genetic variants that were previously unknown that affect CLCNKB and the neighboring gene CLCNKA. In one of the newly discovered structural variants, a small section of one gene was in a similar position in the neighboring gene. The researchers found that the pattern had no immediate effect on the kidneys, but was present in nearly half of the healthy control individuals as well as almost always present in the patients with Bartter syndrome.
“The structural change is fascinating because, in evolutionary terms, it is a mutation hot spot,” says said Janine Altmüller, head of the Genomics Platform of the Max Delbrück Center. “The pattern increases the likelihood that other structural variants could arise during human evolution.”
In fact, the team found eight different deletions in CLCNKB in the patient cohort. What this means, says Altmüller, is that the rare kidney disease does not always result from the same structural variants, but instead involves independent events that share the same genetic background.
The researchers did not discover any additional deleted sequences in the original family, so Bartter syndrome type 3 remained the only diagnosis. But, the new study findings will help scientists better understand the causes of the disease, as well as improve diagnostic and treatment options.