Cell-Free Fetal Deoxyribonucleic Acid (cffDNA) Analysis as a ...
Trisomy 21 Causes Down Syndrome
One could argue that the presence of extra copies of chromosome 21 in DS patients is only a correlation between an abnormality and the disease. However, scientists have developed trisomic mouse models that display symptoms of human DS, providing strong evidence that extra copies of chromosome 21 are, indeed, responsible for DS. It is possible to construct mouse models of DS because mouse chromosomes contain several regions that are syntenic with regions on human chromosome 21. (Syntenic regions are chromosomal regions in two different species that contain the same linear order of genes.) With mapping of the human and mouse genomes now complete, researchers can identify syntenic regions in mouse and human chromosomes with great precision.
As shown in Figure 4, regions on the arms of mouse chromosomes 10 (MMU10), 16 (MMU16), and 17 (MMU17) are syntenic with regions on the long q arm of human chromosome 21. Using some genetic tricks, scientists have induced translocations involving these mouse chromosomes, producing mice that are trisomic for regions suspected to play a role in DS. (Note that these are not perfect models, because the trisomic regions contain many mouse genes in addition to those that are syntenic to human chromosome 21 genes.) These experiments have shown that genes from MMU16 are probably most important in DS, because mice carrying translocations from MMU16 display symptoms more like human DS than mice carrying translocations of MMU10 or MMU17.
Additional experiments have tried to identify particularly important genes within this region by transferring smaller segments of the interval on MMU16. For example, the three mouse models depicted on the right in Figure 4 carry different portions of MMU16, and all display some symptoms of DS. Of the three, the most faithful model of DS is the Ts65Dn mouse, which carries 132 genes that are syntenic with human chromosome 21. This particular mouse demonstrates many of the symptoms of human DS, including altered facial characteristics, memory and learning problems, and age-related changes in the forebrain.
These results are both daunting and promising. On one hand, they suggest that there will be no magic bullet for treating DS, because large numbers of genes are most likely involved in the condition. On the other hand, the results suggest that mouse models will be useful in developing treatments for the many DS patients around the world.
Figure 4: Regions of synteny between human chromosome 21 (HSA21) and mouse chromosomes (MMUs) 16, 17, and 10.
There are three partial trisomy mouse models of human trisomy 21, all trisomic for a portion of MMU 16. The gene content of these partial trisomies is shown on the right.
Long-read Sequencing Reveals New Details Of Bartter Syndrome Type 3
Bartter syndrome type 3 is the result of several structural variants in the genome. By using long-read sequencing, Janine Altmüller and her team from the Max Delbrück Center, the BIH and University Hospital Cologne mapped out the rare disease in unprecedented detail. They have now reported their findings in "Genome Medicine."
When Dr. Bodo Beck first saw the three children of a family who had fled Syria sitting in his consultation room at University Hospital Cologne, the human geneticist was surprised. His genetic analysis diagnosed Bartter syndrome type 3, but never before had he seen such severe joint changes in patients with this rare disease.
The kidney disease is hereditary – affected individuals 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 deletions – areas completely eliminated from the genome – that would explain the severe clinical picture. To find this out would require taking a closer look at the disease-causing genes, so he contacted Dr. Janine Altmüller, head of the Genomics Platform of the Max Delbrück Center and the Berlin Institute of Health at Charité (BIH). Her team, which is based at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB), has pioneered cutting-edge sequencing technologies like long-read sequencing. This technology enabled them to analyze parts of patients' genomes that could not previously be resolved. They have now published their findings in the journal "Genome Medicine."
A tool for analyzing complex structuresTraditional short-read sequencing methods involve breaking up DNA into lots of small fragments, which then have to be reassembled. But when it comes to complex genomic structures, these common clinical technologies reach their limits – such as when sequences are repeated multiple times in a stretch of DNA, as is the case with Bartter syndrome type 3. That explains why no one had previously examined the fine-scale structure of the affected genes.
Long-read sequencing, on the other hand, can accurately read much longer stretches of DNA in a single run, typically in the thousands or even tens of thousands of base pairs. So the individual pieces of this giant puzzle consisting of complex repeating patterns are larger, making it easier to put them back together correctly. It was this advance that led the journal "Nature Methods" to name long-read sequencing its method of the year in 2022.
Using this technology, Altmüller's team of scientists has now 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," says Altmüller. This genetic pattern has no immediate effect on the kidneys and was present in nearly half of the healthy control individuals. But it was almost always present in the patients with Bartter syndrome.
A hot spot for mutationsThe 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. The pattern increases the likelihood that other structural variants could arise during human evolution."
Dr. Janine Altmüller, Head of the Genomics Platform of the Max Delbrück Center and the Berlin Institute of Health at Charité (BIH)
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 Syrian family. So Bartter syndrome type 3 remained the only diagnosis. "In our health care system, we rarely see such an unusually severe disease course," explains Beck. "This is because kidney impairment is typically detected much earlier so that late-stage effects, such as those manifesting in the joints, can usually be prevented."
The findings will help scientists better understand the causes of the disease. Such knowledge may also facilitate the development of better diagnostic and treatment options. 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."
Source:
Journal reference:
Tschernoster, N., et al. (2023) Long-read sequencing identifies a common transposition haplotype predisposing for CLCNKB deletions. Genome Medicine. Doi.Org/10.1186/s13073-023-01215-1.
Bartter Syndrome Type 3 Genetically Decoded
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Bartter syndrome type 3 is the result of several structural variants in the genome. By using long-read sequencing, Janine Altmüller and her team from the Max Delbrück Center, the BIH and University Hospital Cologne mapped out the rare disease in unprecedented detail. They have now reported their findings in "Genome Medicine."
When Dr. Bodo Beck first saw the three children of a family who had fled Syria sitting in his consultation room at University Hospital Cologne, the human geneticist was surprised. His genetic analysis diagnosed Bartter syndrome type 3, but never before had he seen such severe joint changes in patients with this rare disease.
The kidney disease is hereditary – affected individuals 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.
Want more breaking news?Subscribe to Technology Networks' daily newsletter, delivering breaking science news straight to your inbox every day.
Subscribe for FREEIn addition to the absence of the CLCNKB gene, Beck suspected there might be more extensive deletions – areas completely eliminated from the genome – that would explain the severe clinical picture. To find this out would require taking a closer look at the disease-causing genes, so he contacted Dr. Janine Altmüller, head of the Genomics Platform of the Max Delbrück Center and the Berlin Institute of Health at Charité (BIH). Her team, which is based at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB), has pioneered cutting-edge sequencing technologies like long-read sequencing. This technology enabled them to analyze parts of patients' genomes that could not previously be resolved. They have now published their findings in the journal "Genome Medicine."
A tool for analyzing complex structuresTraditional short-read sequencing methods involve breaking up DNA into lots of small fragments, which then have to be reassembled. But when it comes to complex genomic structures, these common clinical technologies reach their limits – such as when sequences are repeated multiple times in a stretch of DNA, as is the case with Bartter syndrome type 3. That explains why no one had previously examined the fine-scale structure of the affected genes.
Long-read sequencing, on the other hand, can accurately read much longer stretches of DNA in a single run, typically in the thousands or even tens of thousands of base pairs. So the individual pieces of this giant puzzle consisting of complex repeating patterns are larger, making it easier to put them back together correctly. It was this advance that led the journal "Nature Methods" to name long-read sequencing its method of the year in 2022.
Using this technology, Altmüller's team of scientists has now 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," says Altmüller. This genetic pattern has no immediate effect on the kidneys and was present in nearly half of the healthy control individuals. But it was almost always present in the patients with Bartter syndrome.
A hot spot for mutationsThe 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," says 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, 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 Syrian family. So Bartter syndrome type 3 remained the only diagnosis. "In our health care system, we rarely see such an unusually severe disease course," explains Beck. "This is because kidney impairment is typically detected much earlier so that late-stage effects, such as those manifesting in the joints, can usually be prevented.
The findings will help scientists better understand the causes of the disease. Such knowledge may also facilitate the development of better diagnostic and treatment options. 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."
Reference: Nikolai Tschernoster et al. Long-read sequencing identifies a common transposition haplotype predisposing for CLCNKB deletions". Genome Medicine. (2023) doi: 10.1186/s13073-023-01215-1
This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.
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