Inside Precision Medicine Precision Medicine Long-Read Sequencing Uncovers Genetic Variants in Rare Kidney Disease

Long-Read Sequencing Uncovers Genetic Variants in Rare Kidney Disease

August 24, 2023

Aug13_2018_Getty_656294507_HumanKidney-e1543246188300 — Credit: MEHAU KULYK/SCIENCE PHOTO/ Getty Images

Researchers used long-read sequencing and identified previously unknown genetic variants that affect the gene associated with the kidney disease Bartter syndrome.

The findings are published in the journal Genome Medicine.

“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.

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. The researchers are now taking steps toward translating the technology into the clinic.