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Study Links Harmful De Novo Gene Mutations to More-Severe Autism

By contrast, milder forms of autism are more strongly associated with family history of psychiatric issues
November 04, 2014

A new study explores the idea that autism associated with spontaneous, or de novo, gene mutations tends to involve far more-disabling symptoms and lower IQ than does autism that results from an inherited predisposition to the disorder.

The findings, by researchers with Harvard Medical School and MassGeneral Hospital, provide further evidence that genetics can advance understanding of autism subtypes and shed light on the different needs of those on the autism spectrum.

De novo gene mutations arise spontaneously in the affected individual. They're not found in either parent. They can occur early in prenatal development, and they continue to accumulate in aging cells – including a woman’s eggs and the cells that produce a man’s sperm. As a result, children born to older parents (i.e. from an older egg and/or spermatocyte) tend to have more de novo mutations. Earlier studies have suggested that this explains, at least in part, why autism rates are higher among the children of older parents.

De novo mutations and autism severity
In the new study, the researchers looked for harmful de novo mutations in 618 boys and 152 girls affected by autism. In this case, “harmful” refers to mutations that cripple a gene’s function.

Among the boys with autism, the study found a clear trend: Boys with severe autism symptoms and intellectual disability (IQ below 70) tended to have a high number of harmful de novo mutations. Boys who were unable to complete even a nonverbal IQ test had the highest rate of all. The inability to complete such tests tends to indicate severe behavioral problems, the authors suggest.

By contrast, boys with milder symptoms and higher-IQs had no more de novo mutations, on average, than is seen in the general population.

The number of girls in the study was too small to reliably identify such trends. However, the girls with autism had twice as many de novo mutations, on average, than did the boys with autism. This is consistent with earlier research suggesting that girls need more genetic “hits” before they develop the disorder.

Editor’s note: Autism research continues to be hampered by the inability to find enough girls and women for clinical studies. For more on this subject, see “Leading Experts Meet to Discuss Gender Differences in Autism.”

De novo versus inherited predisposition
To compare de novo mutations with inherited genetic predisposition for autism, the researchers looked at each child’s family history of depression, schizophrenia and bipolar disorder. Previous research has shown that many of the common gene variations that predispose to these psychiatric disorders likewise predispose to autism.

As a group, the boys with milder autism symptoms and higher IQs were indeed much more likely to have a family history of one or more of these psychiatric disorders. (Again, there weren’t enough girls to make a reliable association.)

However, not every child with a family history of mental disorders had a milder form of autism. Nor did every child with a harmful de novo mutation have severe symptoms. In addition, some people affected by autism have a combination of de novo and inherited risk factors, the researchers note.

The findings have important implications for the field of autism genetics, the study authors conclude. "Genetic studies like this have the potential to identify ASD cases that are more likely to share underlying biology," says lead researcher Elise Robinson. "In the future, this could mean more efficient research and treatment development."

For example, genetic studies focused on individuals with severe symptoms might be the most-efficient for finding targets for medical treatments that restore or compensate for a faulty gene.

At the same time, the study of common gene variants associated with milder autism symptoms may yield insights into how individuals develop social-communication skills – and how best to help those who struggle in this area.