Rare mutations key to brain disorders

Severe disease-causing variants often unique to those affected

Many of the mutations that cause brain disorders are not inherited, new research on the genetics of mental retardation suggests, but are rare DNA variants that pop up for the first time in affected people.

A study published online November 14 in Nature Genetics highlights the importance of rare genetic variants in causing disease, and shows that disrupting even one copy of certain genes can have profound consequences for brain development and mental abilities, says James Lupski, a clinical geneticist at Baylor College of Medicine in Houston.

In the new study, researchers led by Joris Veltman, a human geneticist at Radboud University Nijmegen Medical Center in the Netherlands, searched the genomes of 10 people with mental retardation looking for the cause of the disorder. Scientists have recently shown that during sperm production, big chunks of DNA can get lost or duplicated, leading to diseases or disorders in a man’s offspring. The problem gets worse as men age. About 15 percent of mental retardation cases are associated with these missing or repeated chunks of DNA, Veltman says. But the people in the study didn’t have any of these problems.

The researchers wondered if the patients might have new mutations that change single DNA letters instead of disrupting big chunks of genetic material. To find out, the team searched the protein-producing parts of the genomes of the 10 patients and their parents. On average, the researchers found 21,755 different genetic variants in each person, with about 100 new mutations per generation, Veltman says. Then a variety of techniques helped to whittle the catalog down to just those mutations that were present in patients but not their parents, and that were likely to have functional significance.

The team found nine new mutations in the patients, with each person having a mutation in a different gene. Three of the mutations are unlikely to cause mental retardation, since they disrupt genes not known to be involved in brain function or development. But six other genes, including three previously linked to mental retardation in mice, carried mutations that may lead to the disorder.

One boy did inherit a mutation in the JARID1C gene from his mother. But a DNA analysis of the boy’s maternal grandparents revealed that the mutation arose for the first time in the boy’s mother. She was not mentally retarded because the gene is on the X chromosome, giving her a healthy copy of the gene to compensate. But because males have only one X chromosome, her son was affected by the mutation.

Taken together, the results indicate that new mutations are likely to be an important cause of brain disorders such as mental retardation, Veltman says.

Other diseases, especially severe ones, may also result from new mutations, says Rudolf Uher, a psychiatrist at King’s College London. This study identified genes that are so important to brain development that disturbing even one copy is enough to cause mental retardation. New mutations may be less important, however, for more common disorders such as depression, anxiety or eating disorders, he says.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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