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Study Links Subset of Rare Genomic Disorders to Low-level Somatic Mosaicism in Parents

NEW YORK (GenomeWeb) – A study in the American Journal of Human Genetics suggests healthy individuals may pass on somatic mutations present in a small subset of their cells, playing a previously under-appreciated role in the risk of certain genetic conditions.

"Somatic mosaicism is much more common than we realized in transmission genetics," co-first author Ian Campbell, a Baylor College of Medicine graduate student working with senior authors James Lupski and Pawel Stankiewicz, told GenomeWeb Daily News.

Together with colleagues from Baylor College of Medicine and elsewhere, Campbell, Lupski, and Stankiewicz began by using long-range PCR to test DNA from blood samples taken from parents who had two or more children affected by the same rare genomic deletion.

In each case, the same rare deletions identified in the affected children turned up in low levels in one of the apparently healthy parents, supporting the idea that somatic mutations occurring early in development in a small subset of cells can be passed on to the next generation.

When the team used the same personalized primer and breakpoint mapping approach to scrutinize parental DNA from 100 families with a single affected child, it determined that four parents in that group of participants had low-level somatic mosaicism as well — again involving rare deletions that had previously been deemed de novo mutations.

In contrast to mutations that crop up only in germline cells, the study's authors explained, low-level somatic mutations that can be detected in the blood are more likely to appear in other children, since their presence points to a population of cells having undergone mutation early on in a parent's development.

"One thing that we can glean from seeing [the somatic mosaicism] in the blood and also seeing it transmitted to affected offspring is that those two cell lineages — the blood lineage and the germ lineage — are connected during embryogenesis for a relatively brief period," Campbell noted.

Along with the new biological insights it provides, the work may eventually have clinical applications, researchers noted, particularly for understanding how likely it is that a family that has one child with a rare genomic disorder will go on to have another.

The main source of new, inherited mutations was long thought to be DNA glitches that occurred specifically during the production of so-called germ cells (eggs and sperm), the study authors explained. But with recent studies suggesting that somatic mutation-containing cells can coexist alongside mutation-free cells from the same tissue, they became curious about whether somatic mosaicism present at low levels in parents might also influence disease risk in children.

"Very little was known about the low-grade somatic mosaicism because we haven't had sensitive enough methods to detect it, but also to systematically screen [for it]," co-corresponding Stankiewicz, a molecular and human genetics researcher at Baylor College of Medicine, told GWDN.

To investigate that possibility, the researchers began by using array comparative genomic hybridization to verify the presence of rare deletions in children with genomic disorders from two families. In each family, a rare, private deletion was shared in two or more siblings, suggesting parental mosaicism might be at play.

"We knew that mosaicism was one of the most likely answers," Campbell said. "So we were trying to confirm a hypothesis that we had a priori knowledge about."

After designing primers specific to deletions found in the affected children, he and his colleagues used long-range PCR and Sanger sequencing to search for breakpoints corresponding to the same copy number glitches in DNA from parental blood samples.

In both families, the team determined that either the unaffected mother or father carried low levels of the same mutation present in his or her children, apparently explaining the recurrence of each deletion in two or more siblings.

From there, the researchers decided to take a prospective look at samples from families with just one child who'd been diagnosed with a deletion-based genomic disorder to examine a potential role for somatic mosaicism in those simplex cases.

When they used aCGH and breakpoint-focused PCR to assess samples from more than 100 such families, the researchers identified four cases in which a child's deletion was detected in a subset of blood cells from his or her parent's cells.

That type of somatic mosaicism is consistent with low-level mutations arising early in a parent's development, the study's authors explained, producing a subset of reproductive and somatic cells that harbor the genetic glitch. While the number of affected cells is too low to produce outward disease in the parent, the mutation may be passed on from the germline, contributing to disease in one or more children.

The nature of sex cell production in males and females suggests that women who have one child inheriting a low-level somatic mutation are somewhat more likely to have another affected child, the team noted, whereas recurrence risk is a bit lower in fathers with low-level mosaicism.

"If the [mosaic] mutation came from the mom, that's a lot of information to update your expectations about the proportion of her gametes that are mutant," explained co-author Chad Shaw, also based at Baylor College of Medicine. "If she contributes a mutant allele to a child, chances are she's got a lot of mutant eggs."

The researchers are considering the possibility of testing for low-level somatic mosaicism in tissue types representing each of the three cell lineages involved in embryonic development.

By testing blood, urine, and inner cheek swab cells from the same individual, for example, it should be possible to get a sense of when low-level somatic mutations arose in a parent — information that could conceivably help in deciphering recurrence risk in families who have one child with a rare genomic condition.

"You could imagine a future where couples who are really interested in detecting these kinds of events could opt for additional testing," Campbell said, noting that the group has put together an online resource to help in interpreting mosaicism-related recurrence risk.