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researchers note that the findings regarding the contributions of common and rare variants must be confirmed in larger studies.

However, her paper “supports what people have hypothesized for a while,” says G. Bradley Schaefer, MD, Professor of Pediatrics at the University of Arkansas for Medical Sciences, Section Chief of Genetics and Metabolism at Arkansas Children’s Hospital in Little Rock, and senior author of the American College of Medical Genetics and Genomics (ACMG) guidelines on autism testing.

“The idea is that the right combination of little genetic changes can cause autism,” Dr. Schaefer points out. “This paper is one of the first to look at the mechanistics involved.”

Noting that genetic testing currently yields diagnoses in 35% to 40% of cases, Dr. Schaefer predicts the findings may eventually lead to more answers. But for

now, the paper does send an immediate message to geneticists, he adds. “Just because testing doesn’t find an answer does not mean the cause is not genetic. Diagnosis is still potentially achievable in a little time,” he says.

Increasing use of genomic testing and longitudinal studies that confirm Dr. Roeder’s findings may lead to changes in what ACMG guidelines consider first-, second-, and third-tier tests for diagnosing autism, Dr. Schaefer adds.

The findings may represent a shift in thinking about autism. Both Dr. Roeder and Maximilian Muenke, MD, Chief and Senior Investigator in the Medical Genetics Branch of the National Human Genome Research Institute, note that research in recent years has focused on the role of de novo mutations in autism.

“The important idea that most autism is due to common variations is a paradigm shift,” Dr. Muenke says. The

finding that heritability exceeds 50% is also crucial, he notes. “The main cause is not environmental. It’s not TV, not sugar, vaccines, or video games. It is indeed genetics.”

ReferencesGaugler T, Klei L, Sanders S, Corneliu B, Goldberg A,

Lee S, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman C, Devlin B, Roeder K, Buxbaum J. 2014. Most genetic risk for autism resides with common variation. Nat Genet 46;881–885.

Klei L, Sanders S, Michael M, Hus V, Lowe J, Willsey AJ, Moreno-De-Luca D, Yu T, Fombonne E, Geschwind D, Grice D, Ledbetter D, Lord C, Shrikant Mane S, Martin C, Martin D, Morrow E, Walsh D, Melhem N, Chaste P, Sutcliffe S, State M, Cook E, Roeder K, Devlin B. 2012. Common genetic variants, acting additively, are a major source of risk for autism. Nature 511(7510):421–427.

DOI 10.1002/ajmg.a.368172014 Wiley Periodicals, Inc.

A small but significant proportion of children with single-gene disorders

apparently caused by spontaneous mutations actually inherit diseases from unaffected parents who harbor genetic variations in their blood cells, according to recent research.

The phenomenon of mutation-containing somatic cells coexisting with normal cells in blood or tissue, known as mosaicism, may affect up to 4% of parents of children with single-gene disorders, according to research in the August 7 issue of The American Journal of Human Genetics [Campbell et al., 2014].

Discovered decades ago, mosaicism in parents arises during formation of their own egg and sperm cells, or early in the parent’s own embryonic development

when somatic cells divide. If only a small proportion of cells are affected, these mosaic parents may have no noticeable disease, but pathogenic mutations may be passed on from the germline and cause disorders in the next generation.

While mosaicism is well-known and documented in some disorders, its overall incidence had not been measured until now. The study shows “mosaicism happens more frequently than we thought,” says first author Ian Campbell, an MD/PhD student in the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston.

The paper is important because “it puts data to what we’ve always suspected,” adds Nancy Spinner, PhD, Professor of Pathology and Laboratory Medicine

at the University of Pennsylvania in Philadelphia and an expert on mosaicism.

The StudyThe impetus for the study—led by Pawel Stankiewicz, MD, PhD, and James R. Lupski MD, PhD—came from a United Kingdom–based colleague’s request for help in understanding the recurrence of Smith-Magenis syndrome in three children born to one mother and two different fathers. The Baylor researchers tested the mother’s blood with a form of polymerase chain reaction (PCR) that made many copies of the region of DNA where the children’s deletions occurred and found the mutation in some of her blood cells.

When the researchers tested another

RESEARCH UPDATE CONTINUED

TESTING UPDATE

SOMATIC MOSAICISM IN PARENTS MAY CAUSE SINGLE-GENE DISORDERS IN CHILDRENLatest study calculates incidence of parental mosaicism higher than previous research suggests

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family whose two sons each had identical deletions, they found that the father had a small percentage of similarly mutated blood cells that previous genetic tests did not detect.

To see whether parents of other children with apparently de novo mutations might also show mosaicism in their blood, the researchers used the PCR test on blood from members of 100 families to arrive at their suggested 4% rate of somatic mosaicism.

The actual rate of mosaicism is likely higher because the researchers tested only for deletions in the blood, whereas mosaicism can also occur in other tissues and sex cells. The mosaicism rate may be higher for duplications, says Dr. Stankiewicz, Associate Professor of Molecular and Human Genetics at Baylor.

Based on their observations, Campbell et al developed a model that estimates risk of a mosaic parent of a child with a genetic disease having a second child with the same disorder. The model suggests that mosaicism increases risk of recurrence by 10 times or more. However, the researchers emphasize that their tool is experimental and not intended for clinical use.

Finding MosaicismTypically, mosaicism isn’t difficult to find, especially in disorders with dominant inheritance. The molecular lab at the University of Washington (UW) School of Medicine in Seattle routinely tests for mosaicism for point mutations in seemingly unaffected parents whose child has a genetic disease. Simple sequencing can find mosaicism present in at least one in 10 cells, while “molecular labs can find mosaicism at those levels with Sanger sequencing or use of restriction enzyme digestion,” notes Peter H. Byers, MD, Professor of Pathology and Medicine at the UW School of Medicine. “Newer next-generation sequencing strategies can detect one cell with the mutation among 1,000,” he notes.

Dr. Byers says looking for mosaicism in parents of children with lethal forms of osteogenesis imperfecta (OI) is included in routine diagnostics. OI is one of a group

of diseases, which also includes Marfan syndrome and Duchenne muscular dystrophy, with higher-than-average rates of inheritance from mosaic parents. Knowing which parent harbors mosaic mutations enables more precise estimates of recurrence risk, Dr. Byers emphasizes.

Tests Hold Promise for FutureTests to detect mosaicism may be more broadly applied in the future. “We are now approaching [a] point where we can identify [parental mosaicism] as a source of genetic mutation [in a child],” Dr. Byers says. “We now recognize mosaicism for events larger than point mutations.”

Some day, cell-free fetal DNA that is now used to detect chromosomal trisomies may be used in noninvasive prenatal tests for mosaicism, or to see if a mosaic father has passed on a pathogenic mutation to the fetus, notes Dr. Spinner.

Blood is not the only tissue under study for mosaicism, she adds, noting a few researchers have examined brain tissue. Some have used next-generation sequencing to study single cells and understand how they function in their microenvironments, while other

researchers focus on mosaicism in cancer predisposition. “The big question is: what’s the proportion of mosaic tissue that contributes to disease?” she adds.

Since the reported overall incidence of parental somatic mosaicism is still quite low, “but not nothing,” Dr. Spinner predicts that even with new technology and a broader application of it, insurance companies may not pay for its use in everyone unless the costs can be lowered dramatically.

“The next question,” she adds, “is: who should we test in order to make the biggest impact?”

ReferenceCampbell I, Yuan B, Robberecht C, Pfundt R,

Szafranski, P, McEntagard M, Nagamani S, Erez A, Bartnik M,Wisniowiecka-Kowalnik B, Plunkett K, Pursley A, Kang S, Bi W, Lalani S, Bacino C, Vast M, Marks K, Patton M, Olofsson P, Patel A, Veltman J, Cheung SW, Shaw C, Vissers L, Vermeesch J, Lupski R, Stankiewicz P. 2014. Parental somaticism is underrecognized and influences recurrence risk of genomic disorders. Am J Hum Genet 95:173–182.

DOI 10.1002/ajmg.a.368182014 Wiley Periodicals, Inc.

Lab tests to detect somatic mosaicism in parental blood or tissue samples may be more widely used in the future to pinpoint the cause of genetic disorders in children.

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