Directing tiered genetic testing to one side of the family over the other can speed up the time to diagnosis for more carriers and allow more efficient use of resources.
The new method relies on a technique called staged DNA methylation on genes imprinted from mother and father. Photomontage: Journal of Medicine and Public Health.
Cascading genetic testing to one side of the family over the other can speed up the time to diagnose more carriers and make more efficient use of genetic counseling resources, especially when parents are deceased or otherwise unavailable , their researchers report.
The study being conducted in Canada hints that a new hereditary test can determine whether a gene eliminates it cancer inherited unnecessarily from a patient’s father or mother DNA parental, which could improve the detection and management of the disease.
Peter Lansdorp, MD, PhD, of the Center for Research from Cancer BC in Vancouver, Canada, author of the Research; “The presence of parental fingerprints in parts of the genome has been known for a long time,” he told Medscape Medical News.
In addition, the ability of a specific sequencing technology (Strand-seq) to generate a range of variants of DNA that they tend to be inherited together from a single parent has been documented in several studies. “That these two pieces can be put together to map alleles in a patient to one of the parents without the DNA of parents is a big step forward,” said Lansdorp.
Steven JM Jones, lead author, PhD, associate director of bioinformatics at the Center for Research from Cancer of BC, explained: “To steer cascade genetic testing, the test could be used almost immediately, even as a test for Research. It simply indicates which side of the family to focus familial genetic testing efforts on and is internally validated by the patient’s variant and then confirmed by clinical testing in the family.”
low error rate
Determining a parent of origin (PofO) for inherited variants “is essential for assessing disease risk when a pathogenic variant has PofO effects, i.e. when a patient’s disease risk depends on the parent from which it is inherited”, write the authors. An example is the hereditary paraganglioma-phaeochromocytoma syndrome due to pathogenic variants in the SDHD or SDHAF2 genes. People with the variants are at high risk of developing certain types cancer, but only if a faulty gene is inherited from their father. If it was inherited from your mother, there is no increased risk.
The new method is based on a technique called “methylation of the DNA in phase” in the maternally and paternally imprinted genes, as well as in the chromosomal length phase of the gene sequences. DNA.
The team used five “triplets” of the human genome: two parents and the proband (the first person in a family to be genetically tested or advised for a suspected hereditary risk), to test the approach. They showed that the method can correctly identify the PofO with an average mismatch error rate of 0.31% for single nucleotide variants and 1.89% for insertions or deletions (indels).
Promising future and research actions
“We will need to validate this technology for different genes in real-world samples from individuals of different ancestry,” Jones said. The first step is to validate the technology in settings of immediate clinical utility, such as SDHD, where lifelong medical treatment is influenced by knowing whether the variant is inherited from the mother or the father.
“We also want to quickly validate this for common genes of the cancer such as the BRCA1, BRCA2 and Lynch syndrome-associated genes, where PofO prediction may improve the low rates of genetic testing in family members by providing more accurate estimates of their risk of carrying the familial variant.”
Challenges in moving the test into the clinic, Jones said, include scaling up the technology, demonstrating clinical and economic utility over existing testing approaches, “and familiarizing clinicians with a new type of test that routinely addresses this dimension.” provide additional information”.
“Enormously promising technology”
Pathologist Stephen Yip, MD, PhD, of the Institute for Research of Vancouver Coastal Health in Canada, who is collaborating with the authors on other grant-funded projects, noted: “This is hugely promising technology that has immediate practical implications for Research of PofO from a pathogenic locus, especially when the genetic material is only available at the proband,” he said.
However, “rigorous validation against the current gold standard of short-read, triplet next-generation sequencing is needed before clinical implementation,” he said. “This will take time and effort. However, the promise of this technology is well worth it.”
“In addition, there is the possibility of discovering new genetics during testing, which could pose an ethical dilemma,” he noted. “A robust consent and ethics framework and early involvement from an ethicist would be helpful.”
The Research in the laboratory in Lansdorp is financed by the Institute for Research Terry Fox, The Canadian Institutes of Research in Health, the Canadian Foundation for Innovation and the Government of British Columbia.
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