Bartter syndrome is a group of very similar kidney disorders that cause an imbalance of potassium, sodium, chloride, and related molecules in the body. A team of researchers from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Berlin Institute of Health at Charité report they used long-read sequencing and identified previously unknown genetic variants that affect the gene associated with Bartter syndrome.

The findings are published in Genome Medicine in an article titled, “Long-read sequencing identifies a common transposition haplotype predisposing for CLCNKB deletions.”

“Long-read sequencing is increasingly used to uncover structural variants in the human genome, both functionally neutral and deleterious,” wrote the researchers. “Structural variants occur more frequently in regions with a high homology or repetitive segments, and one rearrangement may predispose to additional events. Bartter syndrome type 3 (BS 3) is a monogenic tubulopathy caused by deleterious variants in the chloride channel gene CLCNKB, a high proportion of these being large gene deletions. Multiplex ligation-dependent probe amplification, the current diagnostic gold standard for this type of mutation, will indicate a simple homozygous gene deletion in biallelic deletion carriers. However, since the phenotypic spectrum of BS 3 is broad even among biallelic deletion carriers, we undertook a more detailed analysis of precise breakpoint regions and genomic structure.”

Janine Altmüller, head of the Genomics Platform of the Max Delbrück Center and the Berlin Institute of Health at Charité (BIH), and her team of scientists have identified various genetic variants that were previously unknown that affect CLCNKB and the neighboring gene CLCNKA. Their study encompassed a cohort of 32 patients from kidney centers in Cologne, Marburg, Münster, and London. “In one of the newly discovered structural variants, a small section of one gene is in a similar position in the neighboring gene,” said Altmüller. This genetic pattern has no immediate effect on the kidneys and was present in nearly half of the healthy control individuals. However, it was almost always present in the patients with Bartter syndrome.

The researchers suspect that this pattern in the genome favors the emergence of disease-causing gene variants. “The structural change is fascinating because, in evolutionary terms, it is a mutation hot spot,” said Altmüller. “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, said Altmüller, is that this rare kidney disease does not always result from the same structural variants, but instead involves independent events that share the same genetic background.

The findings will help scientists better understand the causes of the disease. Altmüller has already taken the first step toward translating the technology into clinical practice: “A pilot study will soon begin with partners from Berlin, Hanover, Tübingen, and Aachen in which we want to apply long-read sequencing to a larger cohort of patients with unsolved rare genetic diseases.”

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