PofO prediction may improve low rates of genetic testing in family members by providing more accurate estimates of their risk of carrying the familial variant.
PofO prediction may improve low rates of genetic testing in family members by providing more accurate estimates of their risk of carrying the familial variant.
Without the need for parental DNA, a new hereditary test can determine whether a cancer-causing gene was inherited from a patient’s father or mother, potentially improving disease screening and management.
“The presence of parental imprints in genome regions has long been known,” study author Peter Lansdorp, MD, PhD, of the BC Cancer Research Centre in Vancouver, Canada, told media. Furthermore, several studies have documented the ability of a specific sequencing technology (Strand-seq) to generate a set of DNA variants that tend to be inherited together from a single parent.
“That these two pieces can be put together to assign alleles in a patient to one of the parents without studying the parents’ DNA is a significant advance,” Lansdorp said.
Steven J.M. Jones, PhD, principal author and associate director of bioinformatics at BC Cancer Research Centre, explained, “The test could be used almost immediately for directing cascade genetic testing, even as a research test. It simply directs which side of the family to concentrate familial genetic testing efforts on, and it is internally validated by the patient’s variant and later confirmed by clinical testing in the family.”
Cascade genetic testing directed to one side of the family over the other could shorten the time it takes to diagnose more carriers and allow for more efficient use of genetic counselling resources, according to Jones, especially when parents are deceased or unavailable.
The findings were published online in Cell Genomics on December 21.
Identifying a hereditary variant’s parent of origin (PofO) “When a pathogenic variant has PofO effects, that is, when a patient’s risk of disease depends on which parent it is inherited from,” the authors write.
Hereditary paraganglioma-pheochromocytoma syndrome is one example caused by pathogenic variants in the genes. Individuals with the variants are at a high risk of developing certain cancers, but only if they inherit a defective gene from their father. There is no increased risk if inherited from their mother.
The new method employs “phased DNA methylation” at maternally and paternally imprinted gene loci, as well as chromosome length phasing of DNA sequences.
To test the approach, the researchers used five human genome “trios” — two parents and the proband (the first person in a family to receive genetic testing or counselling for a suspected hereditary risk). They demonstrated that the method can correctly identify PofO with a mismatch error rate of 0.31% for single nucleotide variants and 1.89% for insertions or deletions (indels).
“We will need to validate this technology for different genes in real-world samples from people from different backgrounds,” Jones said. The first step is to validate the technology in scenarios with immediate clinical utility, such as SDHD (succinate dehydrogenase complex subunit D), where knowing whether the variant was inherited from the mother or father affects lifelong medical management.
“We would also like to quickly validate this for common hereditary cancer genes, such as BRCA1, BRCA2, and Lynch syndrome-associated genes, where PofO prediction may improve low rates of genetic testing in family members by providing more accurate estimates of their risk of carrying the familial variant.”
Scaling up the technology, demonstrating clinical and economic utility compared to existing testing approaches, and “familiarizing clinicians with a new type of test that will routinely give this added dimension of information” are among the challenges to moving the test to the clinic, according to Jones.
Pathologist Stephen Yip, MD, PhD, of the Vancouver Coastal Health Research Institute in Canada, commented on the study. Yip was not involved in the study, but revealed that he works on other grant-funded projects with the authors.
“This is an extremely promising technology with immediate practical implications in the investigation of PofO of a pathogenic locus, especially when genetic material is only available from the proband,” he said.
Yip further added that, this is an extremely promising technology with immediate practical implications in the investigation of PofO of a pathogenic locus, especially when genetic material is only available from the proband.
Prior to clinical deployment, however, “rigorous validation against the current gold standard of short-reading, next-generation sequencing of trios is required,” he said. It will take some time and effort. The promise of this technology, however, is worth the effort.
“There is also the possibility of discovering novel genetics during testing, which could pose an ethical quandary,” he added. “A strong consenting and ethical framework, as well as early involvement of an ethicist, would be beneficial.”