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Certain tests better flag fetuses with brain disorder risk

Fetuses with a specific, rare chromosomal aberration have a 20 percent risk of developmental or other brain disorder, new research shows. The work could lead to personalized diagnostics and counseling for pregnant women.

Fetuses with this new balanced chromosomal aberration have a higher risk of developing brain disorders such as autism and mental retardation than previously anticipated, according to the study in the American Journal of Human Genetics.

“We have identified all the people who, as fetuses, were diagnosed with such a chromosomal aberration in Denmark, and we can see that they more often have developed a disease,” says study coauthor Iben Bache, associate professor in the cellular and molecular medicine department at the University of Copenhagen Faculty of Health and Medical Sciences and medical doctor in the department of clinical genetics at Rigshospitalet.

“We have not known which analyses to use to discriminate the fetuses that will be healthy from those that will eventually develop disorders.”

“The previous study, which found a risk of 6-9 percent, mainly looked at congenital malformations and did not include neurocognitive diseases such as autism and mental retardation, which often emerge at a later stage.

“We have therefore been unaware of the extent of the total risk,” says Bache.

“We call these aberrations balanced chromosomal rearrangements, because all the genetic material is still there. There is neither a loss nor a gain of genetic material. The problem is that parts of the genetic material have been exchanged, and that might have caused disruption of an important gene,” explains Bache.

The study is the largest systematic survey of these rare chromosomal aberrations in fetuses, and it also evaluates the methods that can be used for examining them. These chromosomal abnormalities are diagnosed through chorionic villus sampling or amniocentesis by classical chromosomal analysis, where the genetic material is examined in a microscope. This method has been used for the last 40 years, and it is still the method used in most pregnancies globally.

Another method, called chromosomal microarray, is increasingly replacing the method in Danish hospitals. Chromosomal microarray exclusively tests for loss and gain of the genetic material and therefore cannot discover the rare balanced aberrations in the new study. In contrast, the study reveals that modern genome sequencing in most cases will be able not only to detect these balanced chromosomal aberrations but also show whether genes have been damaged.

The researchers carefully examined the Danish health records to find everyone born with a de novo balanced chromosomal aberration since 1975. Each time they found a person with the aberration, they established a control group of five individuals with normal chromosomes, who had been born more or less at the same time to a mother of the same age.

The researchers then visited the majority of the persons to do a health examination and collect blood samples for modern genetic analyses. By comparing the health data of the group with the chromosomal aberrations and the control group, the researchers found two-three times higher risk of developing a neurocognitive disorder in the group with the chromosomal aberrations.

Discovery upends assumptions about birth defects

In addition, the researchers found that the new whole genome sequencing techniques are much better than any other techniques at assessing the health effect of a balanced chromosomal aberration. This is the conclusion after almost identical assessments made by two independent research groups, including a group from the Harvard Medical School.

“We have not known which analyses to use to discriminate the fetuses that will be healthy from those that will eventually develop disorders. Our study shows that by using the new sequencing technologies we can in fact discriminate in a number of cases,” says Bache. “This may greatly affect the diagnosing and counseling of pregnant women carrying fetuses with this specific type of chromosomal aberration in the future.”

Watching baby brains get wrinkly could flag future disorders

Funding came from the Lundbeck Foundation via the Danish National Research Foundation. The study was a collaboration among researchers at the University of Copenhagen doing basic research, all clinical genetic departments in Denmark, and the department of epidemiological research at Statens Serum Institut.

Source: University of Copenhagen

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